Effects of model traumatic injury on hepatic drug metabolism in the rat. VI. Major detoxification/toxification pathways.
A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase. Hepatic cytosolic glutathione S-transferase activity toward a variety of substrates showed a 26-34% decrease at 24 hr after model injury. Hepatic microsomal epoxide hydrolase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was diminished by 53% after model trauma. Both enzymatic activities toward styrene oxide were similarly depressed. The toxicological sequelae of these derangements were illustrated by administering a dose of styrene oxide (300 mg/kg, ip) which was below the threshold dose (350 mg/kg, ip) necessary to produce hepatotoxicity in control animals. Model trauma dramatically enhanced the hepatotoxic effects of the subthreshold dose, as well as the covalent binding of labeled styrene oxide to liver proteins. These findings indicate that traumatic injury renders the animal more susceptible to agents which are detoxified by glutathione S-transferase and epoxide hydrolase. Conversely, model trauma provided almost complete protection from the hepatotoxic effects of a standard dose (200 mg/kg, ip) of bromobenzene. This protection appeared to derive from a post-traumatic alteration of cytochrome P-450 subpopulations that decreased the formation of the potentially toxic 3,4-epoxide metabolite, despite an increase in the cytochrome P-448-mediated generation of the nontoxic 2,3-epoxide. For bromobenzene, the change in cytochrome P-450-mediated activation appeared quantitatively more significant in overall toxicity than the post-traumatic depression of detoxification pathways described above, leading to decreased toxicity in vivo. For other compounds, the combination of post-traumatic influences on cytochrome P-450/P-448 activity and epoxide hydrolase/glutathione S-transferase activities could lead to markedly enhanced toxicity.
D000818:Animals; D001969:Bromobenzenes / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014947:Wounds and Injuries / Q000378:metabolism*
D001969:Bromobenzenes; D004852:Epoxy Compounds; C013690:styrene oxide; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases