Vinyl chloride hepatotoxicity and its alteration by modifiers of hepatic biotransformation in the rat.
Jaeger-RJ; Mullen-FE; Coffman-LJ; Murphy-SD
Excerpta Medica International Congress, Series No. 376, The Prediction of Chronic Toxicity from Short Term Studies (Proceedings of the European Society of Toxicology) 1975 Jun; 17(376):301-308
The effects of inhibitors of ethyl-alcohol (64175) metabolism on vinyl-chloride-monomer (75014) (VCM) hepatotoxicity were examined in phenobarbital (50066) pretreated rats. The effect of inducers of hepatic mixed function oxidase system (MFOS) activity on serum alanine-alpha-ketoglutarate-transaminase (AKT) activity (an index of liver injury) was also measured 24 hours after VCM exposure. Glutathione concentrations were also assayed. The effect of pyrazole (288131) on acute VCM hepatotoxicity in phenobarbital pretreated rats was examined. Holtzman-rats were exposed for 6 hours to 50,000 parts per million VCM. Animals were pretreated before VCM exposure with the MFOS inducers, phenobarbital at 0.1 percent in the drinking water for 7 days or Aroclor-1254 (11097691) at 300 micromoles per kilogram per day by gavage for 5 days. Phenobarbital pretreated rats were administered pyrazole intraperitoneally at doses from 0 to 320 milligrams per kilogram (mg/kg) before VCM exposure. Inhibitors of ethyl-alcohol metabolism, pyrazole (150mg/kg), SKF-525A (62680) (100mg/kg), ethanol (3mg/kg), or disulfiram (97778) (200mg/kg), were administered by intraperitoneal injection immediately before VCM exposure. Male and female rats that were not pretreated were resistant to VCM hepatotoxicity effects on AKT activity which were produced by phenobarbital or phenobarbital plus ethanol. Pretreatment with inducers of hepatic MFOS activity caused sensitivity to VCM injury in males only; 100, 200, and 320mg/kg pyrazole prevented VCM induced serum AKT activity. When inhibitors of ethyl-alcohol metabolism were examined, only pyrazole and SKF- 525A provided protection against hepatotoxicity of VCM. Following VCM exposure, glutathione concentrations increased markedly in control rats but were not associated with liver damage. The authors conclude that chloroacetaldehyde (107200) is the acute hepatotoxin. SKF-525A may afford protection by MFOS inhibition. Pyrazole may decrease hepatic injury by MFOS inhibition and by alcohol- dehydrogenase inhibition. In the industrially exposed worker, chronic ingestion of ethanol might affect the tumorigenicity of VCM.
NIOSH-Grant; Grants-other; Animal-studies; Metabolic-study; Alcohols; Organo-chlorine-compounds; Hepatic-microsomal-enzymes; Liver-damage; Enzyme-inhibitors; Chronic-exposure
Physiology Harvard University 665 Huntington Ave Boston, Mass 02115
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Other Occupational Concerns; Grants-other
Excerpta Medica International Congress, Series No. 376, The Prediction of Chronic Toxicity from Short Term Studies (Proceedings of the European Society of Toxicology)
Harvard University, Boston, Massachusetts