Document zz498eea4KJp4y6pXRDJjgj80

Jitti \/ c fU** TOXICOLOGY AND aHUED YWAAMACOtOOY 49, 505-515 (1979) , Formation and Inactivation of a Chemically Reactive Metabolite of Vinyl Chloride1 D. Pessayre,* J. C. Wandscheer, V. Descatoire, J. Y. Aktigou, AND J. P. BENHAMOU Unit! de Recherchej de Phytiopathologit Hipatiqut (INSERM\ Udpltal Beaujon, 92118 Cttchp, Franc* Received December 18,1978: accepted March 17,1979 Formation and Inactivation of a Chemically Reactive Metabolite of Vinyl Chloride. PtBAvne, D., Wandscheix, J. C., Descatowe, V., Axtkxhj, J. Y., and Bekhamou, J. P. (1979). Toxicol. Appi. Pharmacol. 49, SOS-515. The mechanisms responsible for, and pro* iccting against, mtubolic activation of vinyl chloride were investigated in the rat. When fQrinyt chloride was incubated with hepatic microsomes, a "C-labeled material became irreversibly bound to microsomal proteins; binding required NADPH, was'decreased by CO, SKF 523-A. or glutathione, and was increased by 1,1,1-trichloropropene-24-oxide (TCPO). Inhalation of a S% vinyl chloride atmosphere decreased hepatic cytochrome p-450 and glutathione. Pretreatment of the animals with DDT or phenobarbital (1) in creased in aiiro irreversible binding to microsomal proteins measured in the presence, but not in the absence, ofTCPO and increased the At r/co loss of cytochrome F^450 during inhala tion of vinyl chloride, but (2) decreased the In thro irreversible binding to lO.OOOy super natant proteins and die in t>/twloss of glutathione during inhalation of vinyl chloride. These results are consistent with the views that (I) vinyl chloride is activated by cytochrome P-450 into its chemically reactive epoxide, (2) the epoxide may be inaedvated by epoxide hydrate or by Unding to glutathione, (3) pretreatment with DDT or phenobarbital in creases both the formation rate of the epoxide and its inactivation rate by epoxide hydrate, and (4) cytochrome P-450 destruction Is related to the formation rate of the epoxide, whereas glutathione depletion seems related to only that fraction of the formed epoxide which has escaped inactivation by microsomal epoxide hydrate and has diffused in the cytosol. Vinyl chloride (chloroethylene) is massively observed (Berk et at., 1976). Hepatic used in the manufacture of plastics: Poly angiosarcomas and liver lesions have been merization of this monomer leads to polyvinyl reproduced in experimental animals chroni chloride, the most widely used synthetic cally exposed to vinyl chloride (Torkelson plastic (Berk et at., 1976). In workers et al., 1961; Lester et at., 1963; Viola et at., exposed to vinyl chloride, angiosarcomas of 1971; Maltoni and Lcfemine, 1975; Prodan the liver and/or hepatic fibrosis have been et at., 1975). Several carcinogenic and/or hepatotoxic * This work was supported by Grant 021 R 07 from compounds arc transformed by the hepatic Faculty de Medecine Xavier-Bichat (Universiti de microsomal mixed-function oxidase system Paris VII), and ATP 58--7S-90 from Institut National de la Santi et de la Recherche Mddicale (INSERM). (MFOS) into chemically reactive metabolites 1 Recipient of a fellowship from the Foods d'Etudes that (l) covalently bind in vitro to micro du Corps Medical Hospitalier. somal proteins, (2) covalently bind in vivo SOS OWl-OOSX/TV/OPWOJ-l ISOXWO Copyright ft 1979 by Academic Press; Inc* All riuhu of reproduction in any form reserved. Primed in Great Britain . h (f < P ;* V it it i f iJ- ucc 006512