Dose-dependent induction and suppression of liver mixed-function oxidase system in chlorinated hydrocarbon solvent metabolism.
The effect of continuous exposure to trichloroethylene (TRI), tetrachloroethylene (TETRA) or methylchloroform (MC) on the hepatic mixed-function oxidase system (MFOS) was studied in rats by using 10 000 x g supernatant fraction. Exposure to TETRA for 240 h at 200, 100 and 50 ppm enhanced oxidative conversion from TETRA to trichloroacetic acid. When the animals were exposed for 240 h to 200, 400 and 800 ppm, oxidative conversion from MC to trichloroethanol was elevated. However, elevation was less remarkable with the increase of exposure intensities from 400 to 800 ppm. With TRI, MFOS activities were more critically assessed as a function of duration and dose because the variable response in MFOS activity was observed in preliminary studies when rats were exposed to 400 ppm for 240 h. The MFOS activities in rats exposed to TRI at 50, 400 or 800 ppm for 48 h, 72 h, 168 h and 240 h were measured. The MFOS activities were all suppressed after 48-h exposure irrespective of the exposure concentration. After 72--240 h, suppression was superseded by activation at 50 ppm, while continuity of suppressive state was observed at 800 ppm and transitional state was the case of the exposure at 400 ppm. The possibility that epoxide hydratase would be involved in the metabolism of TRI, but not in those of other two chemicals, was also presented. Based on these findings, mathematical models for TRI and TETRA metabolism were established, which can explain hepatotoxicity appearing only after exposure to TRI at 800 ppm for 168 h or more.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D008111:Liver Function Tests; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008954:Models, Biological; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D006843:Hydrocarbons, Chlorinated; D011506:Proteins; D006899:Mixed Function Oxygenases; D010634:Phenobarbital