Acarbose alone or in combination with ethanol potentiates the hepatotoxicity of carbon tetrachloride and acetaminophen in rats.
Acarbose reduces the absorption of monosaccharides derived from dietary carbohydrates, which play an important role in the metabolism and toxicity of some chemical compounds. We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1). Male Sprague-Dawley rats were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40, or 80 mg/100 g of acarbose, with drinking water containing 0% or 10% of ethanol (vol/vol). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl4 orally or 0. 75 g/kg AP intraperitoneally. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitrosamine (DMN) demethylation. The 40- or 80-mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40- or 80-mg/100 g acarbose diet alone potentiated CCl4 and AP hepatotoxicity, as evidenced by significantly increased levels of both alanine transaminase (ALT) and aspartate transaminase (AST) in the plasma of rats pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40- or 80-mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potentiation of CCl4 and AP hepatotoxicity was augmented. Our study demonstrated that high doses of acarbose, alone or in combination with ethanol, can potentiate CCl4 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.
Wang
P Y
PY
Department of Environmental Health, Medical University of Yamanashi, Tamaho, Yamanashi, Japan.
Kaneko
T
T
Wang
Y
Y
Sato
A
A
D020909:Acarbose; D000082:Acetaminophen / Q000633:toxicity*; D000477:Alkylating Agents / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004128:Dimethylnitrosamine / Q000378:metabolism; D004357:Drug Synergism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D007120:Immunochemistry; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014312:Trisaccharides / Q000633:toxicity*
D000477:Alkylating Agents; D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D014312:Trisaccharides; D000082:Acetaminophen; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D004128:Dimethylnitrosamine; D020909:Acarbose