Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation.
Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.
Kim
Su N
SN
College of Pharmacy, Seoul National University, Shinrim-Dong, Kwanak-Ku, Seoul, Korea.
Seo
Ji Y
JY
Jung
Da W
DW
Lee
Min Y
MY
Jung
Young S
YS
Kim
Young C
YC
D000082:Acetaminophen / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002263:Carboxyhemoglobin / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008752:Methylene Chloride / Q000097:blood; D008862:Microsomes, Liver / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D008752:Methylene Chloride; D002263:Carboxyhemoglobin; D007064:L-Iditol 2-Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione