- Email: [email protected]
Microsomes and Drug Oxidations
Book
reviews
383
as a sourceof detailed information for all those in- Microsomes and Drug Oxidations Proceedingsof the volved in testingfor mutagenicityand carcinogenicity. Third International SymposiumBerlin, July, 1976. Edited by V. Ullrich, 1. Roots,A. Hildebrandt, R. W. Estabrook and A. H. Conney. Pergamon Press, Oxford, 1977.pp. xxxiv + 768.845.00. Handbook of Experimental Pharmacology. Vol. XVI. Experimental Production of Diseases, Part 5. Liver.
Edited by 0. Eichler. Springer-Verlag,Berlin, 1976. In recent years the metabolismof foreign compp. xiii + 377. DM 192,OO. pounds(or xenobiotics)by mammaliansystemshas receivedmuchattention owingto the numberand varThis book is concernedmainly with the processes iety of suchcompoundsin the environmentto which that give rise to pathological conditions,other than man is exposed.The major site of mammalianxenoturnours, in the liver. The first contribution empha- biotic metabolismis the microsomalfraction of the sizesthe toxic effectsof various chemicalagentson liver, although similar but normally lessactive systhe humanliver and, where possible,comparesthese tems are found in microsomesderived from many with experimentally induced lesions of a similar other tissues,including the lung, kidney, intestinal nature. The author doesnot limit himselfto a simple mucosa,skin and placenta. Particular attention has catalogueof similaritiesand differencesbut attempts beenpaid to cytochromeP-450,which is the terminal to correlatethe experimentalmodel with the human oxygenaseassociatedwith the majority of xenobioticdisease.This is an undeniably formidable task, metabolizing enzymes, and much of the volume becausethe experimentalistand the clinician often namedabove is concernedwith the structure,properdiffer in their conceptof the aetiology and mechanism ties and mechanismof action of this haemoprotein. of any given pathological process,but the attempt The book contains nearly a hundred research is relatively successful and bringsinto relief the value papers presentedat the Third International Symof animalexperimentsin promoting an understanding posium on Microsomesand Drug Oxidations held of the mechanisms by which somechemicalsinduce in West Berlin on 21-24 July 1976*.Each paper is hepatic injury in man. The author’s classificationof supplementedwith a list of referencesand, in addithe major hepatotoxinsas ‘direct’ or ‘indirect’ seems tion, a subjectindex for the entire volumeis provided. of doubtful relevance,since the compoundsin both A glanceat the impressivelist of participantsreveals groupsappear to require somemetabolicconversion that all the major American, Europeanand Japanese to an active intermediate.In particular, there is clear researchgroupswerewell representedat the meeting. experimentalevidence(cited in this contribution) that The papersare groupedinto three broad sections. carbontetrachloride,classedasa directly acting hepa- Whilst the 48 papersin the biochemistrysectiondeal totoxin, exerts its toxic effect through a metabolite. almostexclusivelywith aspectsof cytochromeP-450, Experimentaland humanresultsare alsocompared thosein the pharmacologysectioncover severaladin the contribution on radiation-inducedhepatic in- ditional areas.For example,a numberof papershere jury, and again one cannot help noticing the close dealwith the metabolismof polycyclic hydrocarbons similarity betweenthe rodent liver and the human and particularly with the propertiesof aryl hydroorgan in the responseboth to externally appliedradi- carbon hydroxylase in various tissues.Other papers ation and to radiation from parenterallyadministered considerthe propertiesof epoxide hydrataseand the conversion of xenobiotics to reactive metabohtes, radionuclides. The One contribution dealsentirely with liver diseases which bind covalently to tissuemacromolecules. due to infection and allergy. The wealth of material induction of inhibition of the metabolismof various presentedis taken almost exclusively from human xenobioticsby other chemicalcompounds,by nutricasesand will interest both the pathologist and the tional factorsand in certain diseases is alsodiscussed. clinician. Although this sectionis not of direct rele- The third section,entitled “Outlook”, consistsof six vanceto toxicology, it may be usefulto the patholo- papersin which the authors speculateon possible gist involved in reading pathological material from future advances.The topicscoveredincludethe regutoxicity tests, by providing some insight into the lation of humanxenobiotic metabolismby nutritional obscureand puzzling findings occasionallyencoun- factors, the bay-region theory of aryl hydrocarboninducedcarcinogenesis, the useof in vitro teststo pretered in the liver in such tests. This book is clearly aimedtowardsan understand- dict potentialchemicalcarcinogensand futher aspects ing of the mechanismsof toxic injury. The topics of the purification and mechanismof action of cytoselectedcover a wide rangeof naturally occurringdis- chrome P-450. Thus the researchpaperspresentedin this volume easesand chemically induced lesionsof the human liver. Lesionsinduced in experimentalanimalshave provide the reader with an insight into the state of beencarefully selectedto complementavailableinfor- knowledgein various areasof xenobiotic metabolism mation on the relatedhumancondition. There should in 1976.However, it must be emphasizedthat the be a placefor this volume on the shelvesof clinicians book doesnot constitutea review of xenobiotic metaconcernedwith liver injury and diseaseand it would bolism, since,for the most part, the papersdo not be a good companion,too, for toxicologistsinterested considerbasicprinciples.Whilst, on this account, it in the art of extrapolating animal data to man. cannot be recommendedas an introduction to the subject of xenobiotic metabolism,it must be consideredessentialreading for those actively engaged * The previoussymposia in thisseries wereheldin 1968 in this area of research.Finally, in comparisonwith someother highly priced publicationsin the field of and 1972(Cited in F.C.T 1970, 8, 546; 1975, 13, 270).
384
Book reviews
beyonda given point in a life table, and its variance, or to calculatethe meansurvival time from a group of observations,with its standarddeviation. In the next four chapters the authors discussin Survival Distributions: Reliability Applications in tbe detail the distributions that can be fitted to failure Biomedical Sciences By A. J. Grossand V. A. Clark. rates in a variety of circumstances;apart from the John Wiley & Sons Ltd.. New York, 1976. pp. normal and log-normal,theseincludethe exponential and logistic models and the gamma, Weibull and xv + 331.f14.60. Rayleigh distributions.They show how to fit them Many papershave beenpublishedon survival and to uncensoreddata (in which all the individualsunder reliability theory-the annotatedbibliography in this observationhave died)and to censoreddata (in which volume lists nearly two hundred-but, surprisingly, all the individualshave not died).Fitting thesedistrithis is the first book on the subject.The authors,both butions relieson maximum likelihood methods,but professorsof biostatistics.interpret and co-ordinate alternative mathematicaland graphicaltechniquesare the various methodsthat have been developedfor given for the accurateselectionof survival distribuanalysingsurvival data. Their examplesare drawn for tions to fit a given set of observations. Chapter 7 describesproceduresfor comparingtwo the mostpart from clinical sources,but there is much in the book that can beappliedequally well to labor- survival distributions. These cover parametric and atory experiments,and it is perhapsa fault that this non-parametrictests and censoredand uncensored is not spelt out as clearly as it might have been.A observations.The authors usea signtest for matched little more guidance on this point could have samples,the Wilcoxon test for independentsamples and the likelihood ratio test, using maximum likeliextendedthe book’srangeof usefulness. There are biologistswho have cometo regardany- hood estimation, as a parametric test. Sequential thing mathematicalasnot for them,a conviction that comparisonsare also discussed. Determinationsof appropriate sample size, conmust be strengthenedby the current range of books that are concernedwith statisticsbut promiseat the sideredin the final chapter, are governed by rather start not to call for mathsbeyond O-level standard. different considerationsin clinical and laboratory The authorsnamedabove makeno suchconcession. situations,but in both casesit is essentialto know Instead,they presenta readablebook so plannedthat the lower limit of the required sample size. The eachchapteropenswith an introductory sectionand samplesizeestimatecan then be comparedwith the thengoeson to developpoints in detail. Anyone con- realistic samplesize, which takes into account limicerned with the subjectand wanting to understand tations imposedby cost, facilities, staff and so on, the thinking behindthe analysescould cope with the and if the samplesizeestimatedis lessthan the realisintroductory sections,and a hesitantbiologist might tic size, the study can go ahead.If not, somemeans well read the book for theseparts alone, and then must be sought to bring the estimatedand realistic go on to the more detailedcalculationsapplying to samplesizestogether; it is uselessto start a study his particular field. The book has a contribution to with numberstoo small to give any usefulinformamakeon this level, and although it is intended pri- tion. marily for statisticiansin the biomedicalfield, the exThis could prove a valuablebook for anyoneneedperimentalbiologist could also come to rely on it. ing to interpret survival data. With its broad general The authors start with a general introduction, survey of the field and its detailedexamplesof specific definingthe death densityfunction as the probability cases,it is well within the scopeof the averagebiolothat an individual dieswithin a specifiedinterval, the gist. survivorshipfunction asthe probability that the individual survivesat least to a specifiedpoint in time, and the hazard function as the probability that an individual dies within a specifiedinterval provided he hassurvivedto the start of that interval. The death BOOKS RECEIVED FOR REVIEW density function in biology is the unconditional failProgress in Genetic Toxicology. Developments in Toxiure rate of reliability theory, and the hazard function cology and Environmental Science. Vol 2. Editedby D. is termedthe failure rate whenapplied to thingslike Scott, B. A. Bridgesand F. H. Sobels.Elsevier/Northelectric-light bulbs. Holland BiomedicalPress.Amsterdam,1977. pp. Theseprobabilitiesmay be obtainedby calculation xi + 335.Dfl. 96.00. for any of the various distributionsthat describethe Trace-element Contamination of the Environment. By D. pattern of survival observed in an experimental Purves.ElsevierScientificPublishingCo.. Amsterdam, group. Chapter2 is concernedwith life table analysis 1977.pp. xi + 260.Dfl. 85.00. of survival data, and ,it is pointed out that analyses Directory of On-going Research in Cancer Epidemiology of this kind are in many casessufficient, and that 1977.Editedby C. S.Muir andG. Wagner.IARC Scientific Publicationsno. 17. International Agency for “in fact, only a very small percentageof clinical Research on Cancer,Lyon, 1977.pp. xi + 599.SW.fr. studiesis presentlyanalyzedby techniquesother than 25.00(availablein the UK throughHMSO). those presentedhere”, i.e. life table methods.Most Residues in Food. Reoort of the 1976 Joint Meetof the proceduresdescribedin this chapter can be Pesticide ing of the FAO Panel of Eiperts on Pesticide Residues followed usinga modestpocket calculator. This inand the Environment and the WHO Expert Group on cludesthe methodof E. L. Kaplan and P. Meier using Pesticide Residues Tech.Rep.Ser.Wld. Hlth Org. 1977, orderedobservationsinsteadof .groupeddata to esti612,pp. 35. SW.fr. 6.00(availablein the UK through mate the probability that an individual survives HMSO). foreign-compound metabolism, this one must be considered good value for money.
reviews
383
as a sourceof detailed information for all those in- Microsomes and Drug Oxidations Proceedingsof the volved in testingfor mutagenicityand carcinogenicity. Third International SymposiumBerlin, July, 1976. Edited by V. Ullrich, 1. Roots,A. Hildebrandt, R. W. Estabrook and A. H. Conney. Pergamon Press, Oxford, 1977.pp. xxxiv + 768.845.00. Handbook of Experimental Pharmacology. Vol. XVI. Experimental Production of Diseases, Part 5. Liver.
Edited by 0. Eichler. Springer-Verlag,Berlin, 1976. In recent years the metabolismof foreign compp. xiii + 377. DM 192,OO. pounds(or xenobiotics)by mammaliansystemshas receivedmuchattention owingto the numberand varThis book is concernedmainly with the processes iety of suchcompoundsin the environmentto which that give rise to pathological conditions,other than man is exposed.The major site of mammalianxenoturnours, in the liver. The first contribution empha- biotic metabolismis the microsomalfraction of the sizesthe toxic effectsof various chemicalagentson liver, although similar but normally lessactive systhe humanliver and, where possible,comparesthese tems are found in microsomesderived from many with experimentally induced lesions of a similar other tissues,including the lung, kidney, intestinal nature. The author doesnot limit himselfto a simple mucosa,skin and placenta. Particular attention has catalogueof similaritiesand differencesbut attempts beenpaid to cytochromeP-450,which is the terminal to correlatethe experimentalmodel with the human oxygenaseassociatedwith the majority of xenobioticdisease.This is an undeniably formidable task, metabolizing enzymes, and much of the volume becausethe experimentalistand the clinician often namedabove is concernedwith the structure,properdiffer in their conceptof the aetiology and mechanism ties and mechanismof action of this haemoprotein. of any given pathological process,but the attempt The book contains nearly a hundred research is relatively successful and bringsinto relief the value papers presentedat the Third International Symof animalexperimentsin promoting an understanding posium on Microsomesand Drug Oxidations held of the mechanisms by which somechemicalsinduce in West Berlin on 21-24 July 1976*.Each paper is hepatic injury in man. The author’s classificationof supplementedwith a list of referencesand, in addithe major hepatotoxinsas ‘direct’ or ‘indirect’ seems tion, a subjectindex for the entire volumeis provided. of doubtful relevance,since the compoundsin both A glanceat the impressivelist of participantsreveals groupsappear to require somemetabolicconversion that all the major American, Europeanand Japanese to an active intermediate.In particular, there is clear researchgroupswerewell representedat the meeting. experimentalevidence(cited in this contribution) that The papersare groupedinto three broad sections. carbontetrachloride,classedasa directly acting hepa- Whilst the 48 papersin the biochemistrysectiondeal totoxin, exerts its toxic effect through a metabolite. almostexclusivelywith aspectsof cytochromeP-450, Experimentaland humanresultsare alsocompared thosein the pharmacologysectioncover severaladin the contribution on radiation-inducedhepatic in- ditional areas.For example,a numberof papershere jury, and again one cannot help noticing the close dealwith the metabolismof polycyclic hydrocarbons similarity betweenthe rodent liver and the human and particularly with the propertiesof aryl hydroorgan in the responseboth to externally appliedradi- carbon hydroxylase in various tissues.Other papers ation and to radiation from parenterallyadministered considerthe propertiesof epoxide hydrataseand the conversion of xenobiotics to reactive metabohtes, radionuclides. The One contribution dealsentirely with liver diseases which bind covalently to tissuemacromolecules. due to infection and allergy. The wealth of material induction of inhibition of the metabolismof various presentedis taken almost exclusively from human xenobioticsby other chemicalcompounds,by nutricasesand will interest both the pathologist and the tional factorsand in certain diseases is alsodiscussed. clinician. Although this sectionis not of direct rele- The third section,entitled “Outlook”, consistsof six vanceto toxicology, it may be usefulto the patholo- papersin which the authors speculateon possible gist involved in reading pathological material from future advances.The topicscoveredincludethe regutoxicity tests, by providing some insight into the lation of humanxenobiotic metabolismby nutritional obscureand puzzling findings occasionallyencoun- factors, the bay-region theory of aryl hydrocarboninducedcarcinogenesis, the useof in vitro teststo pretered in the liver in such tests. This book is clearly aimedtowardsan understand- dict potentialchemicalcarcinogensand futher aspects ing of the mechanismsof toxic injury. The topics of the purification and mechanismof action of cytoselectedcover a wide rangeof naturally occurringdis- chrome P-450. Thus the researchpaperspresentedin this volume easesand chemically induced lesionsof the human liver. Lesionsinduced in experimentalanimalshave provide the reader with an insight into the state of beencarefully selectedto complementavailableinfor- knowledgein various areasof xenobiotic metabolism mation on the relatedhumancondition. There should in 1976.However, it must be emphasizedthat the be a placefor this volume on the shelvesof clinicians book doesnot constitutea review of xenobiotic metaconcernedwith liver injury and diseaseand it would bolism, since,for the most part, the papersdo not be a good companion,too, for toxicologistsinterested considerbasicprinciples.Whilst, on this account, it in the art of extrapolating animal data to man. cannot be recommendedas an introduction to the subject of xenobiotic metabolism,it must be consideredessentialreading for those actively engaged * The previoussymposia in thisseries wereheldin 1968 in this area of research.Finally, in comparisonwith someother highly priced publicationsin the field of and 1972(Cited in F.C.T 1970, 8, 546; 1975, 13, 270).
384
Book reviews
beyonda given point in a life table, and its variance, or to calculatethe meansurvival time from a group of observations,with its standarddeviation. In the next four chapters the authors discussin Survival Distributions: Reliability Applications in tbe detail the distributions that can be fitted to failure Biomedical Sciences By A. J. Grossand V. A. Clark. rates in a variety of circumstances;apart from the John Wiley & Sons Ltd.. New York, 1976. pp. normal and log-normal,theseincludethe exponential and logistic models and the gamma, Weibull and xv + 331.f14.60. Rayleigh distributions.They show how to fit them Many papershave beenpublishedon survival and to uncensoreddata (in which all the individualsunder reliability theory-the annotatedbibliography in this observationhave died)and to censoreddata (in which volume lists nearly two hundred-but, surprisingly, all the individualshave not died).Fitting thesedistrithis is the first book on the subject.The authors,both butions relieson maximum likelihood methods,but professorsof biostatistics.interpret and co-ordinate alternative mathematicaland graphicaltechniquesare the various methodsthat have been developedfor given for the accurateselectionof survival distribuanalysingsurvival data. Their examplesare drawn for tions to fit a given set of observations. Chapter 7 describesproceduresfor comparingtwo the mostpart from clinical sources,but there is much in the book that can beappliedequally well to labor- survival distributions. These cover parametric and atory experiments,and it is perhapsa fault that this non-parametrictests and censoredand uncensored is not spelt out as clearly as it might have been.A observations.The authors usea signtest for matched little more guidance on this point could have samples,the Wilcoxon test for independentsamples and the likelihood ratio test, using maximum likeliextendedthe book’srangeof usefulness. There are biologistswho have cometo regardany- hood estimation, as a parametric test. Sequential thing mathematicalasnot for them,a conviction that comparisonsare also discussed. Determinationsof appropriate sample size, conmust be strengthenedby the current range of books that are concernedwith statisticsbut promiseat the sideredin the final chapter, are governed by rather start not to call for mathsbeyond O-level standard. different considerationsin clinical and laboratory The authorsnamedabove makeno suchconcession. situations,but in both casesit is essentialto know Instead,they presenta readablebook so plannedthat the lower limit of the required sample size. The eachchapteropenswith an introductory sectionand samplesizeestimatecan then be comparedwith the thengoeson to developpoints in detail. Anyone con- realistic samplesize, which takes into account limicerned with the subjectand wanting to understand tations imposedby cost, facilities, staff and so on, the thinking behindthe analysescould cope with the and if the samplesizeestimatedis lessthan the realisintroductory sections,and a hesitantbiologist might tic size, the study can go ahead.If not, somemeans well read the book for theseparts alone, and then must be sought to bring the estimatedand realistic go on to the more detailedcalculationsapplying to samplesizestogether; it is uselessto start a study his particular field. The book has a contribution to with numberstoo small to give any usefulinformamakeon this level, and although it is intended pri- tion. marily for statisticiansin the biomedicalfield, the exThis could prove a valuablebook for anyoneneedperimentalbiologist could also come to rely on it. ing to interpret survival data. With its broad general The authors start with a general introduction, survey of the field and its detailedexamplesof specific definingthe death densityfunction as the probability cases,it is well within the scopeof the averagebiolothat an individual dieswithin a specifiedinterval, the gist. survivorshipfunction asthe probability that the individual survivesat least to a specifiedpoint in time, and the hazard function as the probability that an individual dies within a specifiedinterval provided he hassurvivedto the start of that interval. The death BOOKS RECEIVED FOR REVIEW density function in biology is the unconditional failProgress in Genetic Toxicology. Developments in Toxiure rate of reliability theory, and the hazard function cology and Environmental Science. Vol 2. Editedby D. is termedthe failure rate whenapplied to thingslike Scott, B. A. Bridgesand F. H. Sobels.Elsevier/Northelectric-light bulbs. Holland BiomedicalPress.Amsterdam,1977. pp. Theseprobabilitiesmay be obtainedby calculation xi + 335.Dfl. 96.00. for any of the various distributionsthat describethe Trace-element Contamination of the Environment. By D. pattern of survival observed in an experimental Purves.ElsevierScientificPublishingCo.. Amsterdam, group. Chapter2 is concernedwith life table analysis 1977.pp. xi + 260.Dfl. 85.00. of survival data, and ,it is pointed out that analyses Directory of On-going Research in Cancer Epidemiology of this kind are in many casessufficient, and that 1977.Editedby C. S.Muir andG. Wagner.IARC Scientific Publicationsno. 17. International Agency for “in fact, only a very small percentageof clinical Research on Cancer,Lyon, 1977.pp. xi + 599.SW.fr. studiesis presentlyanalyzedby techniquesother than 25.00(availablein the UK throughHMSO). those presentedhere”, i.e. life table methods.Most Residues in Food. Reoort of the 1976 Joint Meetof the proceduresdescribedin this chapter can be Pesticide ing of the FAO Panel of Eiperts on Pesticide Residues followed usinga modestpocket calculator. This inand the Environment and the WHO Expert Group on cludesthe methodof E. L. Kaplan and P. Meier using Pesticide Residues Tech.Rep.Ser.Wld. Hlth Org. 1977, orderedobservationsinsteadof .groupeddata to esti612,pp. 35. SW.fr. 6.00(availablein the UK through mate the probability that an individual survives HMSO). foreign-compound metabolism, this one must be considered good value for money.