Methanol potentiation of carbon tetrachloride hepatotoxicity: the central role of cytochrome P450.
Evidence to explain the enhanced hepatotoxicity of carbon tetrachloride (CCl4) following methanol exposure by inhalation is presented. Hepatic microsomes prepared from male F344 rats exposed to methanol at concentrations up to 10,000 ppm showed increased p-nitrophenol hydroxylase activity but no increase in pentoxyresorufin-O-dealkylase or ethoxyresorufin-O-deethylase activities. Hepatic antioxidant levels, glutathione levels and glutathione-S-transferase activity in methanol-treated animals were not different from controls. In vitro metabolism of CCl4 was also increased in microsomes from methanol-treated animals. Pretreatment with allyl sulfone, a specific chemical inhibitor of cytochrome P450 2E1, abolished the difference in microsomal metabolism between exposed and control animals. This study shows that methanol exposure induces cytochrome P450 2E1, which appears to be the principal toxicokinetic mechanism responsible for the increased metabolism and thus the increased hepatotoxicity of CCl4.
Allis
J W
JW
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Brown
B L
BL
Simmons
J E
JE
Hatch
G E
GE
McDonald
A
A
House
D E
DE
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004357:Drug Synergism; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008107:Liver Diseases / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D000432:Methanol / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D013858:Thiobarbiturates / Q000378:metabolism
D007527:Isoenzymes; D013858:Thiobarbiturates; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; C029684:thiobarbituric acid; D000432:Methanol