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Advances in renal pharmacology: xenobiotics effects on renal function
256 The same group of workers who idet+ t&d the fetal alcohol SyndtVmewere also first to describe a cluster of anomalies in children exposed fatally to hydantoin anti-convulsants.suchas phenytoin. which they designated the ‘C’al hydantoin syndrome“. The syndmtw is characterizedby speciticcraniofacial anomalies, hypoplasia of the digits, with growth, ~v~op~tai and mental retardation. As in the fetal alcohol syndrome,the structuraldefectsate mild and it is lhe functionaland intel@ctuai impairmentswhich .im ofgreatest concent. At 2 yearsof age. signi~~nt im~i~m of grossand fine motor co-ordinationand poor language acquisition have been fwnd, while in children invesoigatedat 7 years of ageJQ scores were lower thanmatchedCOW t&s. 1Q def%its have not been found in offspring of epileptir: wamen taking phenobarbitone. which strongly points IO phenytoin rather than !he epilepsy itself as the behavioural teratogen. Narcotics such as herSn and methadone have also been implicated as behavioural teratogensa’U.Besides~suducinga characteristic withdrawal syndrome in neonates born to narcoticsaddicts. there is some evi dence in the children of disturbedsleep patternsand hyperactivity up to 2 years of age and more persistentproblems causing difticuhiis in sshoolwork, suchas shortattention spans. However. there are olher con. founding variables such as abuse of other drugsand poor nutrition during pregnancy. maternal smokingand drug treatmentof rhe neonatal wiU&awal symptoms, which are CScuit to disentangle from thr. possible effects of the opiatesthemsetves. Similarly, a number of studies have shownthat anaestheticand analgesicdrugs usedduringfabourare associatedwith mod. &cations in infant behaviottr, but many have methodological shortcomingswhich prevent precise delineation of the nature and extent of the changes at thi:i point in time‘s**. Et&cc have been noted in the fmt month of life on infan; suckhtg behaviour, mother-infant inieractions. irritability. habituation,orientiw responses am-t akWtess. whilst in large. lon~te~ fotiLw-np studiesto 7 years of age, delays in motor development, language develop nbmt and acquisition of cqnitive skills havebeen fotmd. In view of the prevalence of obstetric lotion, this area clearly warrants further study.
Then?can now bz Wle doubt that some drugs have the potential to interfern with brain development in such a way as Itopo. duce tiut&o& and behaviotuai defEits in the absenceOf gross strucmraldeformities. The appearanceof hebavioumldisordersin
children may be months or even years removed fmm the ~~ipi~ting prenatal events, so discovery of behavioural teratogensis unlikely from casual observe. don. except where casesmay be clustered, as in prenatalmethylmercurypoisoningand cerebral palsy in Japan, or whete there may be an additional marker such as facial dyrc ~~ogy seen in the fetal alcohol and hydantoin syndromes. However, evidence to date suggeststhat for methyhnercury, alcohol and phenytoin. effects in animals are very similar to those observed in humans. Thus, we may hope that carefully conthllled animal studiesmay be of useful predictive value for evahratiim of the postnatal effectsof drugs used in pregnancy. Reading I&t
I
Hamed, B. K.. Hemiib\n. H. C. and Bnrmr. J) C. (lyJO)Am. /. Med. Sci. HIO. &I6 2 Werhoff, J amJ Gottlicb, J. S. (1%3) Uhsfe?. r;vnu,or. smv. l8.426423 3 Lewis. P. 0.. Pdlel. A. I., B&&k.0, and Balhzs. R. (l~771fk~er i. 399401 4 Lundhnrg, P. nnd Engel, 1. (19771 inAdwnrrs in the Dtw&n of Congenifof Mulfona~ions (van ~~~~~. E. B., Tesh. J. M. SKIFam, G. M.. ois), pp. w-106. Eutapemt Tcnmlwy Swiety. lark. Esnr
bdvances in renal pharmacology:
Mroduct&n whether involving undesirable effects of Tbe general topics of renal $3rmacoldrugs or actions producedby environmenogy and toxi~logy have becomeextremety tal cont~inants, is pmving to be a most diverse. Both the quantityof material availactive and fruitful researcharea at the pree able as well as its variety preclude a ent time. Hence, a brief discussionof some thoroughreview of thesetopics. For exam aspects of renal toxicology also will be pie, the whole area of renal prostaglandins included in this perspective. and other intrarenal hormoneswonld corn-prise a topic for review entirely by Bself, Renal pharmac&rgy from the mid- 1950s e.g. .seeAnnual Review of PtttmwcoiDiuretic therapy has been in and out of ogy and To.rico~ogy , I98 I. vogue throughou\medical history. Perhaps In general,the xenobioticsthat alter renal the most dramatic effects in modem diurefun&on are comprised of chemicals that tic therapy in the U.S.A. were related to the produce both desirable or undesirable introductionof the organomercurialdiureeffects. Some brief eommentson the diure tics in the 192Cts.These substancesserved tics, especially the more modern, useful as the maimtay ofdiuretic therapy for many oneswill representan examinationof desir- years, indeed, extending into the I96Os. able renobiotics’. U~s~b~ effects ate Wipite the acceptance~f~gan~~urials alsopmducedby drugs, but mostoften such as effective therapeuticagents, it was long efftits a thought of as egging to the t~~gnized that thy possesseda variety of reala~ OA&ions caused by environmental disadvantagesranging from the htconven. coWuninants. Renal toxicology, therefore, ience involved in their administration to
l’It?Y -June I982 pmbiems of severe toxicity. None~hetess. in the absence of other agents that couid effcctive!y mobilire large volumes of edema fluid, the organomemuriala proved desirable, indeed at times life saving. thempcuticagents. In the 1950.4a revolution was to occur in diuretic therapy. This came fmm the camful and deliberatestudiesby the scientistsat the Merck. Sharpe and Dohme Company which resukd in the development of the First of a long series of benzothiadiazine diuretics, commonly refetred to as the thiazides. These substances proved revolutionary because they offeted the therapist imponant ~~~ol~~ai and toxicoiog~al ~h~~te~stics not realized with other agents. For example, the carbonic anhydrase inhibitors, which were developed earlier than the thiazides. had some of the same dmwbacks as did the organomercurial diuretics. Specifically. critical mainteme of acid-base balance in the subjects receiving the drag was important for optimal therdpy. and with catbonic anhydraseinhibitorseven optimal therapy often was incapable of mobilizing sufftcient quantities of fluid and electro lytes. The thiGdes, however. proved to be efftcaciousagents(Table I) of only moderate toxicity and with remarkabie and effectiveness. Cerdiniy, under ideal conditions one could mobilize larger quantities of fluid and electrolytes with an organomereurial compound than with a thiazide. but for most situations the thiazides quickly became the drug of choice becauseof theu oral effectivenessand low toxicity. Refractoriness to the thiazides was not demon. snabie with sizable changes in aeid-t~~ balance as was the case for the oganometcurials and the carbonic anhydrate inhibitors. Hence. the thiazidesappearedto overcome all of the major disadvantages associatedwith the organomercurialdim+ tics. Some would argue, however, that for the thiazidesthe bestwas yet tocome. Later in the 1950s imd in the early I96Os it became increasingly clear that the thiazidcs wem remarkably effective at lowering elevated blood pressure.Although not always efteclive as a sole therapeuticagent in casesof severe hy~~ension, the thiaeide class of drugs soon became a mainstay .in antihypertensivetherapy, often being used as the first thempeuticmodality when diet or .saltrestriction would not cause the blood pressureto fall to normal. indeed. in modem tkrapeutic situationsit is likely that the d&ides an: usedmom c~~iy to manage mild hypertensive disease thtm to mobilize fluid and electrolyte in the patient with decompensutedcardiac function or other edematousstates.
25’ The mdustrial chmm5 were not MIS f& with the thiazides as the only effective gmup of diuretic agents. so plan!, were male at the chemical bench to design and develop even mom effiacious sub&tnces. Fmm these efforts a group of substances known as the ‘highceiling diuretic*’ have develofh?dof *bich furosemide and &a~~~~~~~0~~~. Rolh substances resulted from deliberate attempts to make mom effmaciousagents. Although in n%rosfn~tone might argue IMI some of the rea~ning that went into the design of the chrm+zai n~rueture~mirtht have been a bit fanciful. at the time WIWI thesedesignswere propmed the arguments appeamdIogical and consi~ent. Ethaetynie acid. for example. contains a ckmicai grouping that will react with pmtein bound sulthydryi groups in renal tissue. Such a design WF;PI proposedbecauseof the longheld belief that the action of the nrgano. metmnial compounds was related to the intention of memury with tissue suifhydryl groups.Enaddition.ethiuxynicacid had incorpomtedinto it an organicanionic moi ety which presumably would factlitatr it\ delivery to the kidney throughactive tubu lar secretion by the renal organic anion mechanism. Whatever the value of this theoreticalapproach. few can deny the suecess of ethacrynic acid and fumsemide a\ high ceiling agents. These agents can mobilim larger quaotities of fluid and electrolytesthuncan otkr diuretic agentsincludingtheorgaoomercurials given under optimal conditions(Table I). The diuretic response is not readily limited by moderatechangesin gk~memlar fihration or renal blood Row. The diureticls are as effective in metabolic alkalosis as in metabolic acidosis. Indeed. a greater concern might be that the diuretic responsr:to these highceiling agents is frequently not self limiting. a bituationthatmight pre3eflta hazard to some patients. especiaity those using the dmg on an outpatient basis, Nonetheless, these agents are uxd fr+ quently and effectively to mobilize edema
%ud as rrli as IO maodpc elrvated bk& pressure. Over the gear%a mator problem u tth all diuretic thempy has &en the disruption,d twmnidfluid andelec*oiytc balance. In particular. aitr;llions tn plasma pot*sium have heen troubkrurme. parti~ulariy WICK such dteratnnn can fmquently potentum th- effectsof other drugs that might k me6 concmmntiy with diuretrs. For exampte alterati~ms in ptaima potassium can curtainly alter the effects of digitalis alkakotd~ on the heaft and maintlrname of normal pkoma potassium comentmttrmz during drurctictherapyha\ ken a continuing&alIcngc. An innovativeapproachto this dtfft cuity came with tk ~vcl~~nt of the *caJhrl pc&sstum qmng dmrctcs. These agcna cslst in tag iqms: qcrotdal suhtances with an anti-aldoctertnrecffcct. and non-steroidal agents. The ante aktosterooe compounds. La euamptc. spironotactonc.were 6k=velopedto do u bat tkir name Ttgects. t&it IS, couotefactthe effects of &klzterone. Spin~oolactone tames a mniest mcrea5e m u&urn. chloride and uawr I-3 ha dcrrs ~KMprtb motepo?insiumexcretim.Tk M NI~XW&I wlntanceb. ilhllt~~ and amilonde. produced ~tmilar overall effect\ to ~~~1~;~ but act by a c~mplctely driferent m&anisr~. ~~q~~t~~h1~ _ spironolactoneacts hy Mw~ mg tk effect\ oi aktosterore on the kidne?. :ndeed. UI experimental animals *ht..% ba\e ken adrenaiectomized.the acttor(of ~pnonolactone is blocked. Although the nr~n+teroktai compound5produce simrtar ttriniir) excretion patterns In dhr.e produccti h ~pironoiactone.dte~ ~omp~un& do not act hy blocking ihe etfects of aldostemne on the kidne? rrr other lttc\. Apparently the norc~tsroklal agents act b> hleching s4ium tmntpotl at that cite in the nephron wkre pota.sium secretion wcun. Tk blockadeof -.&urn reah~?rpttonat thawsite r‘ausesB dtrrtpation of the electrochemic;il gradient u h:ch normally t%4itate~ p’t& *turn dchve?, mm the nephron; th;rt ISI.
258 c~~~entr;tt~ngabiJity . tubular proteinuria, glucosuria. etc. am all obsetvcd with an ultiNtatcsignificant depressionof glomerular filtration, The damage to the kidney is local&d in the proritttal tubule. RenttJtoxJeobJJy Appamntly. a nutjor accessmute for the The toxic effects of drugs and chemicals aminoglycosfdesinto the renal tubular cells on tonal futtction have long been of is by pincicymsis,along boththepars rerfo intern&. h&cd, untif the advent of and convohtted parts of the proximal hemodialysis,renal failure was repOttedas tubule. Although it has been stqtgestedthat an all too ftequentcauseof human momlity basolntenl uptake of aminoglycosidesmay after the ingestion of various organic sol- occur. the uptake processis not fhoroughly vents, heavy metals. etc. The kidney understOod.The aminoglycosidesas a class appears IO be patticulafly sensitive to the are concentmtcd in renal cotlical tissue. effects of exogenouscompounds.ptobdbly but. in general. there is a poor correlation and nL@tnh becauseof the Jargepercentageof the car- &twOzn tissue ~~ntr~i[~n diac output with whiih it is perfused. In toxicity. Unce inside the c&Is. the aminoaddition. the kidney has the capacity to produce a very concentmtcz tubular fluid glycOsidesseem to bc acc~nu~l~tedin Jyso and. hence, any exogenoussubstattcespm somcs. Indeed. at least a significantpart of sent in that tluid potentially would be pres the nephrotoxicity may be as a result of a ent in very high concentrations. Despite disruption of lysosomal function perhaps nutnemusefforts to de&be the acute renal involving ph~~spholipidmetah4ism. In failure syndmme ~orn~ni~ by acute addition. tbe ami~gly~si~s may exert tubular necmsis in tesponseto exo_genous ditecf effects on rnit~~~nd~al function chemicals,much information is still lacking resultingin a disruptionofencrgy metabolconcerning fundamental mechanisms of ism within the renal cells. thesetoxic responses. Cephalotidine. one of the cephalospnin The complexity of renal function and antibiotics, has been demonstmtedto pas sfntcture no doubt underlies the confusion sess nephmtmic potential in several with respectto ~hanisms of nepbmfoxic- speciess.Most of thecephalos~ns arc not ify. At feastfhrce major cell types appearto so obviously nephrotoxic. bowever. make up the proximal tubuleand thistubule ahhough some suggestionhas been raised section has at least two major anatomical with some of the other compounds, e.p. components. Similarly, cellulifr structure cefazolin. The primary site of disruption and presumably function vrc quite varied caused by cephaloridine appearsto be the through tbe loop of Henle and in the distal proximal tubule, which is that segmentof segmentof the nephrottas well. Since pre- tk nephronrespmtsiblefor the transportof cise mles for the diffe~nt cell types in nor- organic anions. Inte~tingly, unlike many mal renal biochemistry and physiology Of the cephaJosJ.mrin antibiotics. cephalhave yet to be elucidated, their precisemle ondine is not secreted by the mammalian in the pnxlucfion of a nephrotoxic syn- kidney, an observation which stands in dmme is similarly obscure. Whatever these m&ted contrast to the renal handling of precise mechanisms, remarkably similar tk penicillins and other cephalosporin toxic responses are observed after the counpounds. admini~mtion of v~ousd~gs, rna~~~ Tune has developed a considerablebody exogenouschertticals.or substancesadded ofevidence to suggestthat ~ithoughnet secto c~urcnvimnnfentby Mother Nature. In at retion of cephtdoridifledots not occur, this least some of lhese instances it would substanceis transported actively info the appearthatintrarenalorextrarenal metabol- renal tubular cells. Cephabridine is ism may be important in the generationof accumulated to high concentrationsin the nephrofoxicity, while in other instances renal cortex and the extent ofaccumulation mefa~lism of the offending agrnt may be can be correlatedwith the degmeof nephm unim~~ant. Various examplci of these toxicity. The ~c~nism of accumula diverseeffectsare cited below. tion of ccphaloridine is presumablyby the Drug-induced nqhroro.sMy. Several organic anion transpon system since pro of the antibioticsare good examples of the bcnecidpmtteatmentreducedttte accumula. types of ncphnttnxicityproducedby drugs. tinn. In addition. probenecid reduced the The aminoglycosidecompntnds have been nephrotoxicresponse. Exact!y what cepha~oridinedoes within known for some time to be nephmtoxic in man as well as other animals”‘,‘.fn getferal. the renal tubul~cell to producr renal tubuagents in the out-patient clfOic. The newer the overall renal dysfunction produced by lar necrosishas been the subjectof consid agents have been developed IO provide these agents icrnot unlike that seen with erable d&ate. Tune’s group has suggested more safety and predictability in tire diure- other nephrotoxinsin terms of overall renal that this antibiodc hasdirectefRctson renal tic msponse.TJtrOughboth reducedgeneral function. That is to say, decreasedurinary mitochc~ndriitlfunction. Whether the . ...ri-
.sodium reabsofpfi0n is, at ieast in p”ln, for ~~~~ of the potassium secretory gradient. Hence, the appmpriafe elecftochemicai gradtint needed for the secretion of potassium disappears affd although sodium excretion in the urine is enban&. potassiumexcretion is not. Neither dte anti-aldot.terottesubstance nor the nott4eroidal potassium sparing chums are ocularly effe&e diutetic agents when compared to the thiazides or the highcciling substances&thle I). The utility of dtea agentshas been in those refractory edematous states when? Other agents are if&ecfive or under tJtosccifcutnstanceswhen one migJttwant to corn bine a ~~siu~s~ng agent with artodter diuretic. Theoretically. this latter OpJxoachis valid becauo: it allows one to obtain the larger nattiuretic effect Of one diuretic but, dtrough the incorporatior~of the potassiumsparing comoottnd, potassium excretion is not et..tanced. This affords the ~unify for dte excretion of Jarge quantities of sodium. chlnride and water. but withuut the probtemof the large potassiumloss. The most mcent innovation in diumfic therapy was slmrtlived in the clinics of the U.S.A. Tinafen has many of tbe &sirabteeffectsofthe thiaxid....andhighccifing compounds a+. in addition, causes a dramatic incre~ .r in uric acid excretion. This latter actL$ttrepre~nts a major change in tbe action5 of iiureti< substattces. Almost all of thr G:I :r diumtics cause an elevation in blood uric acid. possibly througJtblockade of urve secretion. Ticry&en and other relateJ sffbsfances ato prodffcea significanturicosuria. P&taps thiseffect is most striking when one teahzes that the action on mte excretion is pmduced even in those animals that are normally refractory to tne cJfectsof all! of the cofnmonly usrd uricosuric agents. For exatnple. the mongrel dog respondspoorly Or not at all to probettccidand related compounds but tcsJmndsto ticrynafen with a large increase in urinary mate excretion. This agent is no longer used in the C.S.A. for therapeutic purposes because of sus per%zdseveretoxicity problems. However, other r&ted agentsmay well be 2eveJopcd for use in this country, and most certainly suchagentswill be usedin other pam of the world. Over mcent years modem diuretic therapy has been directed mom and more toward the use Of safer and safer agents, ahho@ concern has been expressed about the extensive use of highly effiacious ~spOttsi&
toxicity and a mom prcdiitable diuretic responsegeneraJJysafer and more reliable fhempeuticup~ttoaches can be undertaken.
hotic is added directly to ntitochondriain vim of mitnchondna are isolated from animals that have ken pretreated with the antibiotic. appmximatcly the bame rehuhh are obtained: state 3 nzspiration and the t~spiratorycontml ratioh which result from the oxidationof the natumlly occurrinl! sub stratcs are rcduccd signilicnntl)“. These data have been taken to mean tkt the necrosis resultingfrom ccphaloridinLadmIni+ tration is the result of .antibi.)tir-in:Iuc~~ mitochondrial dysfunction and ith. *uh~~quentfailureof normal energy nir*talw&m. Other workers”.’ have sugge:btetlthat cephaloridine must be mctaholtzcd IO a reaclive inlennerliate before a toxic effect can be observed.Forexample. inhibitomof the cytochmme P-4-W system rppear IO reducethe liverand renal tnxicity 01 several thiophenes, suggesting that metah~li~m of these compounds is necessaryfor the pm duction of the toxic moiety. However. direct evidencefor a reactive metabolite has no1 been demonstrated. In addition, cephaloridine does not deplete renal gluIathior&, a result usually considered essential to the reactive intermediate hypothesis if that intermediate is to be formed within the renal parenchyma. In addition, it is notewonhy that cephalothin which has a thiophene ring as does cephaloridine, is virtually non-toxic when testedin comparisonwith cephaloridine. Hence, althoughsomecontroversyexists concerning the lmssibility of a reactive intermediate in the case of cephrloridine. the bulk of the Jata suggestthat neither the aminoglycosides nor the cephalosporins require metabolismto a reactive speciesfor the production of nephmtnxicity. In hlth cases it would appear that the damage exerted is directly on the mirochondria, at least in patt. and that one of the cnnse quences of this is ir,‘-‘Xtinn of energy metabolism with resultant necrosis. With the cephalosporins.the exIent of accumulation in the renal cortical tissue is very important for correlation with nephrotoxic response. Such a correlation is not so clear-cut wiIh the aminoglycosides. although whereis no question thawthese agentsenter the target cells. IX. the pmximal tubular cells. Although ItIe details of acetaminopheninducedtoxicity are far from clear, the mlr of metabolism in that event beems to be reasonably well established. This analgesic, when ingested in very large doses, can result in acute pmximal tubular necmsis. Inhibition of the cytochmme P-450 systemcauseda reduction in degree of necrosisproduced. Irreversible. presum ably covalent, binding of label after the administration of tritiated acetamincohen tendsto confirm the mle of metabolisn~ in
the prcxltn~ion01 renal nccn*Iz. % cob.ilcnt hmding occur\ only in ~hctarget organ\ for acetammophen-inducednecnnis. I c. liver and kidney. and not in no&target II+ hue%such a\ bkcletal muxlr. The cxtc;n of cnvalcnt binding parallclcd renal nccrosI\. Signilicant covalent binding cncurrcJ. houevcr. only atier plutathtonc was $I:nilicantly depleted. Thih &es of crh~n~lions
is that inlcrpr~lcxi IO mean acctaminophcn is ccmvcrlcd to a cknucal species which ordinarily reacts uuh ghuathione IO inactivrte the rcactivc qxics prior to eacrction. L’nder circumstances whrn glutathionc depletion hdh
occurred either hccaur of excc\\Ivc dl~\ of acclaminophenor ior other reastmr. Ihe activaled analgesiccan hind irrcvcnihly to imponant cellular macromoleculesrc the isolated perfused kidney. Such a sj\tcrn precludes activation of the anslgeii.: hj hepalicenzyme systems. The above examplesof drugsthat induce nephmtoxicity whether administereJ in normal or large doses highlight the importance of both direct toxic effect3 of the drugs and toxic effects generrltec.by ccacrive metabolitcs. Indeed, the data with acetaminnphen indicate that the ki+ey itself may be an important organ it3r metabolismof xenobiotics.with a ca:‘&ilhy of activalins as well as inactivai “1; :cr:ain chemical species. Nun-drug itadutrd neplm~rr~.wir_r. Several examples of industrial chcmicalb
farm animal*. and it has hccn wgp*tcd
that
one 4~ hah may bc InvolvLd In the pr~nh~~ lion nt the humrn diuar.
cndcmic Balhan ncphropathy The mechaniwnc underlyIng 11 productionof the aculc lubular necro\ir hy thesecompcrund~arc as unclear a* unh other ncThrotorIns. httl the d.ttado u~upgc~ al leasI in w. the role at a ieactibe mIzr_ mcdute. Citnmn dcpletcshcPaticanti rcnrl glutathionc. an c\cnt uhrch precL&\ rhc omct of a ncphrotoxic rc\ponw. In&cd. lhe maximal nephroIo*i~ rcrpmw I\ rhlcvrxi af~crrenal and hqxmc glutdhuux conccntr~tion\ hare rctumcd to n~mni~lor
cben ;I~IW normal In .utditi.3n.c~~\dlenlerr ~rrevzn~hlr bIndIng ot raJlt*acII\rt! aitcr the admmIrtr&m of [ “Cjcitnnrn has keen Jcmon\IIatrrl. The hIndIns 13mlrrr Prom& ncnt in rrndl ti>\uusand reachc* d p~ah m .I matter of an hour or w after ;rdmmI!,IratIon of the compwnd. Although co\alcnt hmding doe\rs;cur in tint liver. chcmapnitudc of the binding is much ler\ Ihan that m Ldnq an ohrvatinn cnnrirtent ulth the Iach of cvhiencc for hepatic d> \function aficr the admimstratlon ofcmmm.
In conimt ro the \tuJIe\ unh acetammophen. cIudic\ unh the iudatcd perfuud kidnq t Bcrndt. unpubl&cd observations). sugge\t that thcrc I> n,, metrbohsm of citrimn I+ the 14&d LI&
ney. The abscncr of drntionsI&& Intrs renal formation of mcuhrhtes and ?SI the cffcct of thI\ ComptunJ ,rn tI\\ur: glutathionr and the prcwncr ot ~o~.~lcnr binding presnt a puzrlc Thc*c J.ua ma! Indicate that glutaIhIonc JcpletIon d&/or cotalcnt binding hu\c no rclau~m\hip to the production of ncphroI~~\IcIt~ . or .4,mc
and other environmenlal pollutants u ith effects on renal function can he cite& In
mechanism for the pnniucuon 61:w mtrs rcndl mctaholitc cxlsts \rhich I\ ethrr thdn
patticular. the halognatcd hydmc$bon compoundsare most nnteaonhy. De_unJing upon the species,dose. circum*taI:‘:e:rf dosing. etc., chhnhm and carh)n tztrachloride can be demonsIratedto lo ncphrc~ toxic. Although the data arc circum\ldn-
direct acti\&on of the parent
tial. it is disrinctl) posGhlc that the inlr;rrenal metabolism of thcsc t\no hakycn.acd hydrcxarbons may bc wsponuhlr for the
Pensrationof the to\ic mctah~lite*“‘. Naturally occurring suhstancc% also have been reportedto pmduccrenal d) sfunction. Several mycoIoCns. wcond;tr) iungal metabolitrs. havr been implicated in the pmduction of a s*calleu mycoto,rininduced nephropathy”. Of co!~rse.fungal toxins are known to be involved in a number of acute and chnmic toxic events. but the effects of citrinin and ochratoxin A on renal funclion highlight the poIential ,mporiance of these compounds with cspec~to nephrotoxicity. One or both of ~hesr:substanceshave been implicared in rhe production of porcine nephmparhy in
nc.r a \t*nx. bcing Ii!(acI
reactive intermcdiars In Ifi? u~uill Thi> mctahbliIr might. for c\.u~plc. rclati\el~ \tablc. reach Ihc LlJnc! u hcrc funhcr nirlth~liam tKc‘iur* N :rh produ~~h~noi B +lnI.mc~~u+ TL’;~CII\S u\~mp~unJ.rhI5 wconJ.1, phJu(t brmcd in the kidnc) oh\~ou+ \rr~dlJ n’.lI he r\ Idrnl in an ~bola& P13Iuad t&x,> c\l*‘nmcru H hcrc thr parent cnrimn H;I. ;tJJcJIt> the pertu\air. II would h Ihc rcacIIbc intcrmcdiatcfrom the *conJay mct.ih~htc thar would be rcspon.rihlc ior glutclrhlonc depletion and ncphroto*ic$. The ahwe e~~~~plrs demonstrate the variety ofefftyts that can he produced in the
kidney with respecttn nephrotoGcit? Bath and environmenlal pollutants drugs (m-made and n;lrunlly occurring) ma) hc invohrd In some circumstances dir.:
TIPS - Junr I 982
260 the production of the necrotic syndrome of view which highlights ~hckidng as an organ of ~ta~~i~ as well as transport. whereas in other ci~urn~an~s it is neces sary to have formation of a reactive inter- Rigs I Mudge. ci. H. (t9IU)j in TJw Y/u?wwmwlo~ice/ mediate. Furthermom, the pmiiminaty and Bmti of Themptwtics (Ciilman. A. G., Gilman. cimumslantiid data with citrinin suggest A.andGmtman. L..edr),6thedn,pp. tt92-915. that a twostep activation processmay be Mwnillan Publish@Co.. New York responsible,with the fust of theseoccurring 2 Hook. 1. B. (IPttOJin %xiw/agy %dl. J.. in the liver and the secondin the kidney. In Khtawn. C. D. and Amdur. hi. 0.. cd+. 2nd any event,,this brief review was intendedto cdn, pp. 232-246, M~~iiinn ~lt~hi~~ C% NevrYe& point out the ~ibi~~ty of the kidney as an 3 Katoy;lntdw.G. J. snd PtiswiucMtunttt. t%. organ of metabolism h’swell as af excmtI!lnu)!3&ry ml. IS, S7l-582 tion. Many of the effects. both desirable J Morin. 1. P., Viwe. 0.. Vandewittlc.A.. vun (perhaps) and undesirable(cenainly), may Hmf. F.. ‘lidkens.P. and Fitlast~. J. P. (1980) result fmm metabolism of xenobiotics in Kidmy In,. 18.S83-590 the kiiney itself. J Tune. 6. N. wtdFwcil. D. (19801A%f#q ht. Overall, advancesin renal ~~oio~ IS.s991-600 6 ~M~~~ R. 1. and~~11. J. R. t I9?7) Ifoxand toxoid over the pWt several &I. Appt. Pkwwwoi. 42.285-300 decodes appear to have taken :wo major 7 Mitchell.1. R.. hlcMumy. R. 1.. SlaIhnm,C. N. turns. To begin with, them was a period of and Netun, C. 0. (1977) Am. 1. I%. 62, rapid dimtic development fmm the 1950s 518-526 on, dun@ which impottant therapeutic &IMirbell. 1. R.. Hinwn. J. A. and Nelson.S. D. agents Caeredeveloped, tested and proven (1976) in CXutathionr: Uctabol&n and Fwrrin the clinical use. Subsequendy,and most #ion (Aria*. 1. M. and J&by, W. B., edsj. pp. mcently, fu~lio~ studiestelated to tenal X1-367. RavenPress,New Y&i 9 Ross.8.. Twgc, 1.. Ems&z.K.. Hart, S.. Smeit, toxicity seem to be dewing moth attenM. andfahkr. I. ( IPBOfKidneyin?. I& Sbt-570 tion. These studies seem to arise fiwm the generalconcernabout envimnmental con- IO Hook, I. 8.. McCornwk. K. M. iutd Kluwe. W. M. I I979)Rn. Biorhem TuxicoL I. 53-78 taminationanddnig toxicity, but ah mote I I Bemdt. W. 0.. Hayes.A. W. and Phillips.R. D. importandy. fmm a purely scientific point (I9ROfKidnq In;. 18.m
Pharmacology of cigarette smoking behavior Roland R. Griffiths and Jack ELHenningfiefd Dtimnmen:of Byc/U~. TheJohns HoQkitU Univrrsity S&of of,%?ditine, Bolrinro~, .t#t@Vld, Zl.?OS. U.S.A.and A&i&ion Reworch Center. Rex 5200. Bakimwe, MD 21224. U.S.A.
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Despite rhe ubiquityof ci~areuesmoking, the pharmacological dtwnninants of lhis i&&or hove only recemly become a focus of sub~~nii~l researclt efforts. This research hes revealed hunan cigarette ~rn~~n~ to be an orders form of drug ~~~~~n~r~~ which is responsive lo II variety of phurm~log~~l
Tobaccosmokmghasbeenrecognizedas a pbarmacoTogiit~ mediated pattern of behavior by the scholarsof at least 4 ten. turies who described varied medicinal and psychic benefits of smoking’-‘. II was not until the l9Nk, however, that experimental evidence directly impiii nicotine as a detetmintmtof smoking behavior. In 1942, Johnston showed that hypodermically~~~t~~~~~e~ ~ve~~~~ci~~s~~,a~~ the injections were ~+brted to smokit&. A subsequentstudy in 1945 suggestedthat the amotmt of smcking was inversely
related to the nicotinecontentof cigarettes’. These investigationswere seminal in altering the ptqntlar c~ce~~li~t~n of cigarette smoking from that of a predominately psychologically mediated behavior (e.g. a strong ‘habit’) to that of a pharmacologically mediated behavior. Ftmher investigatiousdeveloped relatively slowly until Jarvik, in the U.S.A., and Russell, in the U.K.. independently organimd sy~ tematic research pmgrams into cigarette smoking. A rna+r impetus for such reseamhwas the mqmitfon of serioustoxicological conseqcercesof smoking in the 1960s. A continuing impetus For this
research has been the debate arising from the promotion of low nicotine/tar yield cigarettesas lessharmful. To the extent that smokers tegulate their smoke intake. low yield cigarettesmay producecompensatory mcreascs in smoking which, in turn, increase exposure to some of the toxic chants of smoke (e.g. carbon monoxideP, Although this isstm remains to be satisfactorily resolved. substantial advanceshave been made in understanding the pharmacologicaldeterminantsof smoking behaviop’. Some of these achieve ments will be summarized in this review. fairly
farmof
Fmm casual observation of cigarette smokers,it is clear that there is considerable variation across smokers in amounts, patterns and styles of smoking, and that moment to moment decisions about whether or not to smoke are intluenced by many situat~al and envi~~ntal factors. This individual variation and easy modulationofud li&itumsmokingencouragesa view of smoking as a relatively etratic, inconsistentbehavior under ‘voluntary’ control, and tends to mask the extent to which smoking is an orderly behaviorallocal process. The orderly nature OF smoking emerges clearly when smokmg is studied in regular heavy smokers m&r laboratory conditionslargely free of activities incompatible with smoking.
Then?can now bz Wle doubt that some drugs have the potential to interfern with brain development in such a way as Itopo. duce tiut&o& and behaviotuai defEits in the absenceOf gross strucmraldeformities. The appearanceof hebavioumldisordersin
children may be months or even years removed fmm the ~~ipi~ting prenatal events, so discovery of behavioural teratogensis unlikely from casual observe. don. except where casesmay be clustered, as in prenatalmethylmercurypoisoningand cerebral palsy in Japan, or whete there may be an additional marker such as facial dyrc ~~ogy seen in the fetal alcohol and hydantoin syndromes. However, evidence to date suggeststhat for methyhnercury, alcohol and phenytoin. effects in animals are very similar to those observed in humans. Thus, we may hope that carefully conthllled animal studiesmay be of useful predictive value for evahratiim of the postnatal effectsof drugs used in pregnancy. Reading I&t
I
Hamed, B. K.. Hemiib\n. H. C. and Bnrmr. J) C. (lyJO)Am. /. Med. Sci. HIO. &I6 2 Werhoff, J amJ Gottlicb, J. S. (1%3) Uhsfe?. r;vnu,or. smv. l8.426423 3 Lewis. P. 0.. Pdlel. A. I., B&&k.0, and Balhzs. R. (l~771fk~er i. 399401 4 Lundhnrg, P. nnd Engel, 1. (19771 inAdwnrrs in the Dtw&n of Congenifof Mulfona~ions (van ~~~~~. E. B., Tesh. J. M. SKIFam, G. M.. ois), pp. w-106. Eutapemt Tcnmlwy Swiety. lark. Esnr
bdvances in renal pharmacology:
Mroduct&n whether involving undesirable effects of Tbe general topics of renal $3rmacoldrugs or actions producedby environmenogy and toxi~logy have becomeextremety tal cont~inants, is pmving to be a most diverse. Both the quantityof material availactive and fruitful researcharea at the pree able as well as its variety preclude a ent time. Hence, a brief discussionof some thoroughreview of thesetopics. For exam aspects of renal toxicology also will be pie, the whole area of renal prostaglandins included in this perspective. and other intrarenal hormoneswonld corn-prise a topic for review entirely by Bself, Renal pharmac&rgy from the mid- 1950s e.g. .seeAnnual Review of PtttmwcoiDiuretic therapy has been in and out of ogy and To.rico~ogy , I98 I. vogue throughou\medical history. Perhaps In general,the xenobioticsthat alter renal the most dramatic effects in modem diurefun&on are comprised of chemicals that tic therapy in the U.S.A. were related to the produce both desirable or undesirable introductionof the organomercurialdiureeffects. Some brief eommentson the diure tics in the 192Cts.These substancesserved tics, especially the more modern, useful as the maimtay ofdiuretic therapy for many oneswill representan examinationof desir- years, indeed, extending into the I96Os. able renobiotics’. U~s~b~ effects ate Wipite the acceptance~f~gan~~urials alsopmducedby drugs, but mostoften such as effective therapeuticagents, it was long efftits a thought of as egging to the t~~gnized that thy possesseda variety of reala~ OA&ions caused by environmental disadvantagesranging from the htconven. coWuninants. Renal toxicology, therefore, ience involved in their administration to
l’It?Y -June I982 pmbiems of severe toxicity. None~hetess. in the absence of other agents that couid effcctive!y mobilire large volumes of edema fluid, the organomemuriala proved desirable, indeed at times life saving. thempcuticagents. In the 1950.4a revolution was to occur in diuretic therapy. This came fmm the camful and deliberatestudiesby the scientistsat the Merck. Sharpe and Dohme Company which resukd in the development of the First of a long series of benzothiadiazine diuretics, commonly refetred to as the thiazides. These substances proved revolutionary because they offeted the therapist imponant ~~~ol~~ai and toxicoiog~al ~h~~te~stics not realized with other agents. For example, the carbonic anhydrase inhibitors, which were developed earlier than the thiazides. had some of the same dmwbacks as did the organomercurial diuretics. Specifically. critical mainteme of acid-base balance in the subjects receiving the drag was important for optimal therdpy. and with catbonic anhydraseinhibitorseven optimal therapy often was incapable of mobilizing sufftcient quantities of fluid and electro lytes. The thiGdes, however. proved to be efftcaciousagents(Table I) of only moderate toxicity and with remarkabie and effectiveness. Cerdiniy, under ideal conditions one could mobilize larger quantities of fluid and electrolytes with an organomereurial compound than with a thiazide. but for most situations the thiazides quickly became the drug of choice becauseof theu oral effectivenessand low toxicity. Refractoriness to the thiazides was not demon. snabie with sizable changes in aeid-t~~ balance as was the case for the oganometcurials and the carbonic anhydrate inhibitors. Hence. the thiazidesappearedto overcome all of the major disadvantages associatedwith the organomercurialdim+ tics. Some would argue, however, that for the thiazidesthe bestwas yet tocome. Later in the 1950s imd in the early I96Os it became increasingly clear that the thiazidcs wem remarkably effective at lowering elevated blood pressure.Although not always efteclive as a sole therapeuticagent in casesof severe hy~~ension, the thiaeide class of drugs soon became a mainstay .in antihypertensivetherapy, often being used as the first thempeuticmodality when diet or .saltrestriction would not cause the blood pressureto fall to normal. indeed. in modem tkrapeutic situationsit is likely that the d&ides an: usedmom c~~iy to manage mild hypertensive disease thtm to mobilize fluid and electrolyte in the patient with decompensutedcardiac function or other edematousstates.
25’ The mdustrial chmm5 were not MIS f& with the thiazides as the only effective gmup of diuretic agents. so plan!, were male at the chemical bench to design and develop even mom effiacious sub&tnces. Fmm these efforts a group of substances known as the ‘highceiling diuretic*’ have develofh?dof *bich furosemide and &a~~~~~~~0~~~. Rolh substances resulted from deliberate attempts to make mom effmaciousagents. Although in n%rosfn~tone might argue IMI some of the rea~ning that went into the design of the chrm+zai n~rueture~mirtht have been a bit fanciful. at the time WIWI thesedesignswere propmed the arguments appeamdIogical and consi~ent. Ethaetynie acid. for example. contains a ckmicai grouping that will react with pmtein bound sulthydryi groups in renal tissue. Such a design WF;PI proposedbecauseof the longheld belief that the action of the nrgano. metmnial compounds was related to the intention of memury with tissue suifhydryl groups.Enaddition.ethiuxynicacid had incorpomtedinto it an organicanionic moi ety which presumably would factlitatr it\ delivery to the kidney throughactive tubu lar secretion by the renal organic anion mechanism. Whatever the value of this theoreticalapproach. few can deny the suecess of ethacrynic acid and fumsemide a\ high ceiling agents. These agents can mobilim larger quaotities of fluid and electrolytesthuncan otkr diuretic agentsincludingtheorgaoomercurials given under optimal conditions(Table I). The diuretic response is not readily limited by moderatechangesin gk~memlar fihration or renal blood Row. The diureticls are as effective in metabolic alkalosis as in metabolic acidosis. Indeed. a greater concern might be that the diuretic responsr:to these highceiling agents is frequently not self limiting. a bituationthatmight pre3eflta hazard to some patients. especiaity those using the dmg on an outpatient basis, Nonetheless, these agents are uxd fr+ quently and effectively to mobilize edema
%ud as rrli as IO maodpc elrvated bk& pressure. Over the gear%a mator problem u tth all diuretic thempy has &en the disruption,d twmnidfluid andelec*oiytc balance. In particular. aitr;llions tn plasma pot*sium have heen troubkrurme. parti~ulariy WICK such dteratnnn can fmquently potentum th- effectsof other drugs that might k me6 concmmntiy with diuretrs. For exampte alterati~ms in ptaima potassium can curtainly alter the effects of digitalis alkakotd~ on the heaft and maintlrname of normal pkoma potassium comentmttrmz during drurctictherapyha\ ken a continuing&alIcngc. An innovativeapproachto this dtfft cuity came with tk ~vcl~~nt of the *caJhrl pc&sstum qmng dmrctcs. These agcna cslst in tag iqms: qcrotdal suhtances with an anti-aldoctertnrecffcct. and non-steroidal agents. The ante aktosterooe compounds. La euamptc. spironotactonc.were 6k=velopedto do u bat tkir name Ttgects. t&it IS, couotefactthe effects of &klzterone. Spin~oolactone tames a mniest mcrea5e m u&urn. chloride and uawr I-3 ha dcrrs ~KMprtb motepo?insiumexcretim.Tk M NI~XW&I wlntanceb. ilhllt~~ and amilonde. produced ~tmilar overall effect\ to ~~~1~;~ but act by a c~mplctely driferent m&anisr~. ~~q~~t~~h1~ _ spironolactoneacts hy Mw~ mg tk effect\ oi aktosterore on the kidne?. :ndeed. UI experimental animals *ht..% ba\e ken adrenaiectomized.the acttor(of ~pnonolactone is blocked. Although the nr~n+teroktai compound5produce simrtar ttriniir) excretion patterns In dhr.e produccti h ~pironoiactone.dte~ ~omp~un& do not act hy blocking ihe etfects of aldostemne on the kidne? rrr other lttc\. Apparently the norc~tsroklal agents act b> hleching s4ium tmntpotl at that cite in the nephron wkre pota.sium secretion wcun. Tk blockadeof -.&urn reah~?rpttonat thawsite r‘ausesB dtrrtpation of the electrochemic;il gradient u h:ch normally t%4itate~ p’t& *turn dchve?, mm the nephron; th;rt ISI.
258 c~~~entr;tt~ngabiJity . tubular proteinuria, glucosuria. etc. am all obsetvcd with an ultiNtatcsignificant depressionof glomerular filtration, The damage to the kidney is local&d in the proritttal tubule. RenttJtoxJeobJJy Appamntly. a nutjor accessmute for the The toxic effects of drugs and chemicals aminoglycosfdesinto the renal tubular cells on tonal futtction have long been of is by pincicymsis,along boththepars rerfo intern&. h&cd, untif the advent of and convohtted parts of the proximal hemodialysis,renal failure was repOttedas tubule. Although it has been stqtgestedthat an all too ftequentcauseof human momlity basolntenl uptake of aminoglycosidesmay after the ingestion of various organic sol- occur. the uptake processis not fhoroughly vents, heavy metals. etc. The kidney understOod.The aminoglycosidesas a class appears IO be patticulafly sensitive to the are concentmtcd in renal cotlical tissue. effects of exogenouscompounds.ptobdbly but. in general. there is a poor correlation and nL@tnh becauseof the Jargepercentageof the car- &twOzn tissue ~~ntr~i[~n diac output with whiih it is perfused. In toxicity. Unce inside the c&Is. the aminoaddition. the kidney has the capacity to produce a very concentmtcz tubular fluid glycOsidesseem to bc acc~nu~l~tedin Jyso and. hence, any exogenoussubstattcespm somcs. Indeed. at least a significantpart of sent in that tluid potentially would be pres the nephrotoxicity may be as a result of a ent in very high concentrations. Despite disruption of lysosomal function perhaps nutnemusefforts to de&be the acute renal involving ph~~spholipidmetah4ism. In failure syndmme ~orn~ni~ by acute addition. tbe ami~gly~si~s may exert tubular necmsis in tesponseto exo_genous ditecf effects on rnit~~~nd~al function chemicals,much information is still lacking resultingin a disruptionofencrgy metabolconcerning fundamental mechanisms of ism within the renal cells. thesetoxic responses. Cephalotidine. one of the cephalospnin The complexity of renal function and antibiotics, has been demonstmtedto pas sfntcture no doubt underlies the confusion sess nephmtmic potential in several with respectto ~hanisms of nepbmfoxic- speciess.Most of thecephalos~ns arc not ify. At feastfhrce major cell types appearto so obviously nephrotoxic. bowever. make up the proximal tubuleand thistubule ahhough some suggestionhas been raised section has at least two major anatomical with some of the other compounds, e.p. components. Similarly, cellulifr structure cefazolin. The primary site of disruption and presumably function vrc quite varied caused by cephaloridine appearsto be the through tbe loop of Henle and in the distal proximal tubule, which is that segmentof segmentof the nephrottas well. Since pre- tk nephronrespmtsiblefor the transportof cise mles for the diffe~nt cell types in nor- organic anions. Inte~tingly, unlike many mal renal biochemistry and physiology Of the cephaJosJ.mrin antibiotics. cephalhave yet to be elucidated, their precisemle ondine is not secreted by the mammalian in the pnxlucfion of a nephrotoxic syn- kidney, an observation which stands in dmme is similarly obscure. Whatever these m&ted contrast to the renal handling of precise mechanisms, remarkably similar tk penicillins and other cephalosporin toxic responses are observed after the counpounds. admini~mtion of v~ousd~gs, rna~~~ Tune has developed a considerablebody exogenouschertticals.or substancesadded ofevidence to suggestthat ~ithoughnet secto c~urcnvimnnfentby Mother Nature. In at retion of cephtdoridifledots not occur, this least some of lhese instances it would substanceis transported actively info the appearthatintrarenalorextrarenal metabol- renal tubular cells. Cephabridine is ism may be important in the generationof accumulated to high concentrationsin the nephrofoxicity, while in other instances renal cortex and the extent ofaccumulation mefa~lism of the offending agrnt may be can be correlatedwith the degmeof nephm unim~~ant. Various examplci of these toxicity. The ~c~nism of accumula diverseeffectsare cited below. tion of ccphaloridine is presumablyby the Drug-induced nqhroro.sMy. Several organic anion transpon system since pro of the antibioticsare good examples of the bcnecidpmtteatmentreducedttte accumula. types of ncphnttnxicityproducedby drugs. tinn. In addition. probenecid reduced the The aminoglycosidecompntnds have been nephrotoxicresponse. Exact!y what cepha~oridinedoes within known for some time to be nephmtoxic in man as well as other animals”‘,‘.fn getferal. the renal tubul~cell to producr renal tubuagents in the out-patient clfOic. The newer the overall renal dysfunction produced by lar necrosishas been the subjectof consid agents have been developed IO provide these agents icrnot unlike that seen with erable d&ate. Tune’s group has suggested more safety and predictability in tire diure- other nephrotoxinsin terms of overall renal that this antibiodc hasdirectefRctson renal tic msponse.TJtrOughboth reducedgeneral function. That is to say, decreasedurinary mitochc~ndriitlfunction. Whether the . ...ri-
.sodium reabsofpfi0n is, at ieast in p”ln, for ~~~~ of the potassium secretory gradient. Hence, the appmpriafe elecftochemicai gradtint needed for the secretion of potassium disappears affd although sodium excretion in the urine is enban&. potassiumexcretion is not. Neither dte anti-aldot.terottesubstance nor the nott4eroidal potassium sparing chums are ocularly effe&e diutetic agents when compared to the thiazides or the highcciling substances&thle I). The utility of dtea agentshas been in those refractory edematous states when? Other agents are if&ecfive or under tJtosccifcutnstanceswhen one migJttwant to corn bine a ~~siu~s~ng agent with artodter diuretic. Theoretically. this latter OpJxoachis valid becauo: it allows one to obtain the larger nattiuretic effect Of one diuretic but, dtrough the incorporatior~of the potassiumsparing comoottnd, potassium excretion is not et..tanced. This affords the ~unify for dte excretion of Jarge quantities of sodium. chlnride and water. but withuut the probtemof the large potassiumloss. The most mcent innovation in diumfic therapy was slmrtlived in the clinics of the U.S.A. Tinafen has many of tbe &sirabteeffectsofthe thiaxid....andhighccifing compounds a+. in addition, causes a dramatic incre~ .r in uric acid excretion. This latter actL$ttrepre~nts a major change in tbe action5 of iiureti< substattces. Almost all of thr G:I :r diumtics cause an elevation in blood uric acid. possibly througJtblockade of urve secretion. Ticry&en and other relateJ sffbsfances ato prodffcea significanturicosuria. P&taps thiseffect is most striking when one teahzes that the action on mte excretion is pmduced even in those animals that are normally refractory to tne cJfectsof all! of the cofnmonly usrd uricosuric agents. For exatnple. the mongrel dog respondspoorly Or not at all to probettccidand related compounds but tcsJmndsto ticrynafen with a large increase in urinary mate excretion. This agent is no longer used in the C.S.A. for therapeutic purposes because of sus per%zdseveretoxicity problems. However, other r&ted agentsmay well be 2eveJopcd for use in this country, and most certainly suchagentswill be usedin other pam of the world. Over mcent years modem diuretic therapy has been directed mom and more toward the use Of safer and safer agents, ahho@ concern has been expressed about the extensive use of highly effiacious ~spOttsi&
toxicity and a mom prcdiitable diuretic responsegeneraJJysafer and more reliable fhempeuticup~ttoaches can be undertaken.
hotic is added directly to ntitochondriain vim of mitnchondna are isolated from animals that have ken pretreated with the antibiotic. appmximatcly the bame rehuhh are obtained: state 3 nzspiration and the t~spiratorycontml ratioh which result from the oxidationof the natumlly occurrinl! sub stratcs are rcduccd signilicnntl)“. These data have been taken to mean tkt the necrosis resultingfrom ccphaloridinLadmIni+ tration is the result of .antibi.)tir-in:Iuc~~ mitochondrial dysfunction and ith. *uh~~quentfailureof normal energy nir*talw&m. Other workers”.’ have sugge:btetlthat cephaloridine must be mctaholtzcd IO a reaclive inlennerliate before a toxic effect can be observed.Forexample. inhibitomof the cytochmme P-4-W system rppear IO reducethe liverand renal tnxicity 01 several thiophenes, suggesting that metah~li~m of these compounds is necessaryfor the pm duction of the toxic moiety. However. direct evidencefor a reactive metabolite has no1 been demonstrated. In addition, cephaloridine does not deplete renal gluIathior&, a result usually considered essential to the reactive intermediate hypothesis if that intermediate is to be formed within the renal parenchyma. In addition, it is notewonhy that cephalothin which has a thiophene ring as does cephaloridine, is virtually non-toxic when testedin comparisonwith cephaloridine. Hence, althoughsomecontroversyexists concerning the lmssibility of a reactive intermediate in the case of cephrloridine. the bulk of the Jata suggestthat neither the aminoglycosides nor the cephalosporins require metabolismto a reactive speciesfor the production of nephmtnxicity. In hlth cases it would appear that the damage exerted is directly on the mirochondria, at least in patt. and that one of the cnnse quences of this is ir,‘-‘Xtinn of energy metabolism with resultant necrosis. With the cephalosporins.the exIent of accumulation in the renal cortical tissue is very important for correlation with nephrotoxic response. Such a correlation is not so clear-cut wiIh the aminoglycosides. although whereis no question thawthese agentsenter the target cells. IX. the pmximal tubular cells. Although ItIe details of acetaminopheninducedtoxicity are far from clear, the mlr of metabolism in that event beems to be reasonably well established. This analgesic, when ingested in very large doses, can result in acute pmximal tubular necmsis. Inhibition of the cytochmme P-450 systemcauseda reduction in degree of necrosisproduced. Irreversible. presum ably covalent, binding of label after the administration of tritiated acetamincohen tendsto confirm the mle of metabolisn~ in
the prcxltn~ion01 renal nccn*Iz. % cob.ilcnt hmding occur\ only in ~hctarget organ\ for acetammophen-inducednecnnis. I c. liver and kidney. and not in no&target II+ hue%such a\ bkcletal muxlr. The cxtc;n of cnvalcnt binding parallclcd renal nccrosI\. Signilicant covalent binding cncurrcJ. houevcr. only atier plutathtonc was $I:nilicantly depleted. Thih &es of crh~n~lions
is that inlcrpr~lcxi IO mean acctaminophcn is ccmvcrlcd to a cknucal species which ordinarily reacts uuh ghuathione IO inactivrte the rcactivc qxics prior to eacrction. L’nder circumstances whrn glutathionc depletion hdh
occurred either hccaur of excc\\Ivc dl~\ of acclaminophenor ior other reastmr. Ihe activaled analgesiccan hind irrcvcnihly to imponant cellular macromoleculesrc
farm animal*. and it has hccn wgp*tcd
that
one 4~ hah may bc InvolvLd In the pr~nh~~ lion nt the humrn diuar.
cndcmic Balhan ncphropathy The mechaniwnc underlyIng 11 productionof the aculc lubular necro\ir hy thesecompcrund~arc as unclear a* unh other ncThrotorIns. httl the d.ttado u~upgc~ al leasI in w. the role at a ieactibe mIzr_ mcdute. Citnmn dcpletcshcPaticanti rcnrl glutathionc. an c\cnt uhrch precL&\ rhc omct of a ncphrotoxic rc\ponw. In&cd. lhe maximal nephroIo*i~ rcrpmw I\ rhlcvrxi af~crrenal and hqxmc glutdhuux conccntr~tion\ hare rctumcd to n~mni~lor
cben ;I~IW normal In .utditi.3n.c~~\dlenlerr ~rrevzn~hlr bIndIng ot raJlt*acII\rt! aitcr the admmIrtr&m of [ “Cjcitnnrn has keen Jcmon\IIatrrl. The hIndIns 13mlrrr Prom& ncnt in rrndl ti>\uusand reachc* d p~ah m .I matter of an hour or w after ;rdmmI!,IratIon of the compwnd. Although co\alcnt hmding doe\rs;cur in tint liver. chcmapnitudc of the binding is much ler\ Ihan that m Ldnq an ohrvatinn cnnrirtent ulth the Iach of cvhiencc for hepatic d> \function aficr the admimstratlon ofcmmm.
In conimt ro the \tuJIe\ unh acetammophen. cIudic\ unh the iudatcd perfuud kidnq t Bcrndt. unpubl&cd observations). sugge\t that thcrc I> n,, metrbohsm of citrimn I+ the 14&d LI&
ney. The abscncr of drntionsI&& Intrs renal formation of mcuhrhtes and ?SI the cffcct of thI\ ComptunJ ,rn tI\\ur: glutathionr and the prcwncr ot ~o~.~lcnr binding presnt a puzrlc Thc*c J.ua ma! Indicate that glutaIhIonc JcpletIon d&/or cotalcnt binding hu\c no rclau~m\hip to the production of ncphroI~~\IcIt~ . or .4,mc
and other environmenlal pollutants u ith effects on renal function can he cite& In
mechanism for the pnniucuon 61:w mtrs rcndl mctaholitc cxlsts \rhich I\ ethrr thdn
patticular. the halognatcd hydmc$bon compoundsare most nnteaonhy. De_unJing upon the species,dose. circum*taI:‘:e:rf dosing. etc., chhnhm and carh)n tztrachloride can be demonsIratedto lo ncphrc~ toxic. Although the data arc circum\ldn-
direct acti\&on of the parent
tial. it is disrinctl) posGhlc that the inlr;rrenal metabolism of thcsc t\no hakycn.acd hydrcxarbons may bc wsponuhlr for the
Pensrationof the to\ic mctah~lite*“‘. Naturally occurring suhstancc% also have been reportedto pmduccrenal d) sfunction. Several mycoIoCns. wcond;tr) iungal metabolitrs. havr been implicated in the pmduction of a s*calleu mycoto,rininduced nephropathy”. Of co!~rse.fungal toxins are known to be involved in a number of acute and chnmic toxic events. but the effects of citrinin and ochratoxin A on renal funclion highlight the poIential ,mporiance of these compounds with cspec~to nephrotoxicity. One or both of ~hesr:substanceshave been implicared in rhe production of porcine nephmparhy in
nc.r a \t*nx. bcing Ii!(acI
reactive intermcdiars In Ifi? u~uill Thi> mctahbliIr might. for c\.u~plc. rclati\el~ \tablc. reach Ihc LlJnc! u hcrc funhcr nirlth~liam tKc‘iur* N :rh produ~~h~noi B +lnI.mc~~u+ TL’;~CII\S u\~mp~unJ.rhI5 wconJ.1, phJu(t brmcd in the kidnc) oh\~ou+ \rr~dlJ n’.lI he r\ Idrnl in an ~bola& P13Iuad t&x,> c\l*‘nmcru H hcrc thr parent cnrimn H;I. ;tJJcJIt> the pertu\air. II would h Ihc rcacIIbc intcrmcdiatcfrom the *conJay mct.ih~htc thar would be rcspon.rihlc ior glutclrhlonc depletion and ncphroto*ic$. The ahwe e~~~~plrs demonstrate the variety ofefftyts that can he produced in the
kidney with respecttn nephrotoGcit? Bath and environmenlal pollutants drugs (m-made and n;lrunlly occurring) ma) hc invohrd In some circumstances dir.:
TIPS - Junr I 982
260 the production of the necrotic syndrome of view which highlights ~hckidng as an organ of ~ta~~i~ as well as transport. whereas in other ci~urn~an~s it is neces sary to have formation of a reactive inter- Rigs I Mudge. ci. H. (t9IU)j in TJw Y/u?wwmwlo~ice/ mediate. Furthermom, the pmiiminaty and Bmti of Themptwtics (Ciilman. A. G., Gilman. cimumslantiid data with citrinin suggest A.andGmtman. L..edr),6thedn,pp. tt92-915. that a twostep activation processmay be Mwnillan Publish@Co.. New York responsible,with the fust of theseoccurring 2 Hook. 1. B. (IPttOJin %xiw/agy %dl. J.. in the liver and the secondin the kidney. In Khtawn. C. D. and Amdur. hi. 0.. cd+. 2nd any event,,this brief review was intendedto cdn, pp. 232-246, M~~iiinn ~lt~hi~~ C% NevrYe& point out the ~ibi~~ty of the kidney as an 3 Katoy;lntdw.G. J. snd PtiswiucMtunttt. t%. organ of metabolism h’swell as af excmtI!lnu)!3&ry ml. IS, S7l-582 tion. Many of the effects. both desirable J Morin. 1. P., Viwe. 0.. Vandewittlc.A.. vun (perhaps) and undesirable(cenainly), may Hmf. F.. ‘lidkens.P. and Fitlast~. J. P. (1980) result fmm metabolism of xenobiotics in Kidmy In,. 18.S83-590 the kiiney itself. J Tune. 6. N. wtdFwcil. D. (19801A%f#q ht. Overall, advancesin renal ~~oio~ IS.s991-600 6 ~M~~~ R. 1. and~~11. J. R. t I9?7) Ifoxand toxoid over the pWt several &I. Appt. Pkwwwoi. 42.285-300 decodes appear to have taken :wo major 7 Mitchell.1. R.. hlcMumy. R. 1.. SlaIhnm,C. N. turns. To begin with, them was a period of and Netun, C. 0. (1977) Am. 1. I%. 62, rapid dimtic development fmm the 1950s 518-526 on, dun@ which impottant therapeutic &IMirbell. 1. R.. Hinwn. J. A. and Nelson.S. D. agents Caeredeveloped, tested and proven (1976) in CXutathionr: Uctabol&n and Fwrrin the clinical use. Subsequendy,and most #ion (Aria*. 1. M. and J&by, W. B., edsj. pp. mcently, fu~lio~ studiestelated to tenal X1-367. RavenPress,New Y&i 9 Ross.8.. Twgc, 1.. Ems&z.K.. Hart, S.. Smeit, toxicity seem to be dewing moth attenM. andfahkr. I. ( IPBOfKidneyin?. I& Sbt-570 tion. These studies seem to arise fiwm the generalconcernabout envimnmental con- IO Hook, I. 8.. McCornwk. K. M. iutd Kluwe. W. M. I I979)Rn. Biorhem TuxicoL I. 53-78 taminationanddnig toxicity, but ah mote I I Bemdt. W. 0.. Hayes.A. W. and Phillips.R. D. importandy. fmm a purely scientific point (I9ROfKidnq In;. 18.m
Pharmacology of cigarette smoking behavior Roland R. Griffiths and Jack ELHenningfiefd Dtimnmen:of Byc/U~. TheJohns HoQkitU Univrrsity S&of of,%?ditine, Bolrinro~, .t#t@Vld, Zl.?OS. U.S.A.and A&i&ion Reworch Center. Rex 5200. Bakimwe, MD 21224. U.S.A.
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Despite rhe ubiquityof ci~areuesmoking, the pharmacological dtwnninants of lhis i&&or hove only recemly become a focus of sub~~nii~l researclt efforts. This research hes revealed hunan cigarette ~rn~~n~ to be an orders form of drug ~~~~~n~r~~ which is responsive lo II variety of phurm~log~~l
Tobaccosmokmghasbeenrecognizedas a pbarmacoTogiit~ mediated pattern of behavior by the scholarsof at least 4 ten. turies who described varied medicinal and psychic benefits of smoking’-‘. II was not until the l9Nk, however, that experimental evidence directly impiii nicotine as a detetmintmtof smoking behavior. In 1942, Johnston showed that hypodermically~~~t~~~~~e~ ~ve~~~~ci~~s~~,a~~ the injections were ~+brted to smokit&. A subsequentstudy in 1945 suggestedthat the amotmt of smcking was inversely
related to the nicotinecontentof cigarettes’. These investigationswere seminal in altering the ptqntlar c~ce~~li~t~n of cigarette smoking from that of a predominately psychologically mediated behavior (e.g. a strong ‘habit’) to that of a pharmacologically mediated behavior. Ftmher investigatiousdeveloped relatively slowly until Jarvik, in the U.S.A., and Russell, in the U.K.. independently organimd sy~ tematic research pmgrams into cigarette smoking. A rna+r impetus for such reseamhwas the mqmitfon of serioustoxicological conseqcercesof smoking in the 1960s. A continuing impetus For this
research has been the debate arising from the promotion of low nicotine/tar yield cigarettesas lessharmful. To the extent that smokers tegulate their smoke intake. low yield cigarettesmay producecompensatory mcreascs in smoking which, in turn, increase exposure to some of the toxic chants of smoke (e.g. carbon monoxideP, Although this isstm remains to be satisfactorily resolved. substantial advanceshave been made in understanding the pharmacologicaldeterminantsof smoking behaviop’. Some of these achieve ments will be summarized in this review. fairly
farmof
Fmm casual observation of cigarette smokers,it is clear that there is considerable variation across smokers in amounts, patterns and styles of smoking, and that moment to moment decisions about whether or not to smoke are intluenced by many situat~al and envi~~ntal factors. This individual variation and easy modulationofud li&itumsmokingencouragesa view of smoking as a relatively etratic, inconsistentbehavior under ‘voluntary’ control, and tends to mask the extent to which smoking is an orderly behaviorallocal process. The orderly nature OF smoking emerges clearly when smokmg is studied in regular heavy smokers m&r laboratory conditionslargely free of activities incompatible with smoking.