Inhalation toxicity studies of hydrogen cyanide (HCN) in spbague-dawley rats

136 SUlM’RATE-SPECIFIC SYNERGISTIC INHIBITION OF HEPATIC MIXED FDNCTIUNOXIDATIONBY ASCORBIC H.R. and SWARBLIN, P. ACID AND PARAQUAT. MONTCOWERY,

RESEARCHSERVICE, VA HOSPITAL, 13000

N. 30th

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Substrate-Specific Synergilrtic Inhibition of Hepatic Mixed Function Oxidation by Ascorbic Acid and Paraquat. M.R. Wontgwery and P. Shamblin. VA Hospital and Department of Pharmacology, University of South Florida, Tampa, FL., USA 33620 We have reported previously the synergistic inhibition of mitochondrial oxidative phosphorylation by ascorbic acid and paraquat. The capacity of this redox couple to alter membrane bound electron transfer systems is not limited to mitochondria. Oxidative drug metabolism in hepatic microsomal fractions prepared from male rats is inhibited in vitro -by 0.1 - 1.0 mW paraquat. With 2 M4 ethylmorphine as subrtrate,inclusionof 1.0 - 10.011~ ascorbate did not result in inhibition of N-demathylase which was any greater than that inhibition observed with paraquat alone1 however, with 2nH andline as substrate, inhibition of microsomal p-hydroxylation was potentiated 30% - 60% by inclusion of 1.0 - lO.omM ascorbate. These concentrations of ascorbate alone were without effect on the metabolism of either substrate. To alter the rate of electron flux within the microsomal membrane, a group of rats was pretreated with sodilrm phenobarbital (lmg/kg in drinking water for 4 days). When aniline p-hydroxylase was investigated In these induced preparations,the synergisticinhibitionwas no longer observed at the lower combination of concentrations (0.1 mR parequat plus 1.0 mW ascorbate) but was maintained at the higher combination (0.5 mM paraquat plus 5.0 mW ascorbate). The redox couple, ascorbate - paraquat, will not reduce the cytochrome P450 - CO complex. The rate of NADPHoxidation is stimulated greater by paraquat when aniline is substrate than when ethylmorphine is substrate. Inclusion of ascorbate did not increase the rate of NADPHoxidation beyond that observed with peraquat alone. This study was supported by VA Medical Research funds and NIH grant ES02846.

INHALATIONTOXICITY STUDIES OF RYDROGENCYANIDE (HCN) IN SPRACDE-DAWLEY RATS. ROLWF. WV., SRORT. R.D.. SC2DJENCEL,S.M., AND RIBELIN, W.E.

BLANK, T.L.,

MXiSANTC CCWPARYDEPARIWENT OF FBIDICINll AED ENVIRONWEF CAL HlUU.Tll, RNVIROHMENTALHEALlli

LARORATORY,645 SOWIllNiWXJ3ADAVWUB, ST. LOUIS. MISSOURI, 63110

Five male and five female Sprague-Dawlcy rate ware exposed to HCNsix hours per day for A 4-week study wae later performed with three consecutive daya at 4g pp~ HCN in air. groups of 10 male oad 10 female rats par group at 0. 11, 29 and SEIppm HCN in air. Hypoactivity, niacellaneoua breathing difficulties, aigna of hypoxfa, convulaionn and chraothinorrhea were obaervul only in the three-day study animale. Alao, death reaulted Necropsy findings Included cyanosis in three of the five malea after one day of expoaure. of the axtralties, moderate-to-mvere hemorrhage of the lung end pulmonary adama for the males which died and light-toaerate hmorrhage and gray appaarance of the lung were obaemad in the survivingfemales. In the faar week ~~tudy, no mortality warnobservedat concmtrat1m. up to 58 pp RCN. Rowavery aa the result of a brief excurrion (about 125 ppm for 15 minutes) lmala and 3 fralem died in tha high apomre group. Body waighta were alfghtly raduced (96% of cartrol) only in the huh expoeura Rtoup. Increamd urine thiocyanate levclm ware obeemed in thm rid- and high uxporure groups. No collpoundrelrted effect8 uere evidenced in either clinical, groaa or microscopic pathology. No dverae effectr wre obaanrad in rata exposed to 29 pc to HCNrk houra each waekday for

4 ueeka.