beta-ionone and Chemical-and-Drug-Induced-Liver-Injury

A possible role of metabolic activation by cytochrome P450 (P450) in thioacetamide-induced hepatotoxicity was investigated in male BALB/c mice. The mice were pretreated with the P450 inducer, beta-ionone, subcutaneously at 600 mg/kg, 72 and 48 h prior to an intraperitoneal administration of either 100 or 200 mg/kg of thioacetamide. The elevated activities of serum alanine aminotransferase and serum aspartate aminotransferase by thioacetamide were greatly potentiated by the pretreatment with beta-ionone. Moreover, the potentiation of thioacetamide-induced hepatotoxicity was also observed in the histopathological examination of livers. The hepatic necrosis by thioacetamide was potentiated when mice were pretreated with beta-ionone. In liver microsomes, the activities of P450 2B-specific pentoxyresorufin O-depentylase and benzyloxyresorufin O-debenzylase were significantly induced by the treatment with beta-ionone. Beta-ionone also induced other P450-associated monooxygenases. Because the pretreatment with beta-ionone was not hepatotoxic at the dose inducing P450s. our present results suggest that beta-ionone may be a useful model inducer of P450 enzyme(s) in studying toxic mechanism of certain chemicals which require metabolic activation by P450s in mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carcinogens; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Drug Synergism; Enzyme Induction; Isoenzymes; Liver; Liver Function Tests; Male; Mice; Mice, Inbred BALB C; Microsomes, Liver; Norisoprenoids; Terpenes; Thioacetamide

To investigate the role of metabolism in cocaine-induced immunosuppression, diazinon and beta-ionone were administered as an esterase inhibitor and a cytochrome P-450 (P-450) inducer, respectively, to B6C3F1 female mice. When 10 or 30 mg/kg of diazinon was administered 30 min before cocaine (30 mg/kg) was administered i.p. for 7 consecutive days, the suppression of the T-dependent antibody response to sheep red blood cells was potentiated greatly when compared to the suppression by cocaine alone. Spleen and thymus weights were decreased significantly and serum glutamate-pyruvate transaminase activities were elevated dramatically when cocaine and diazinon were administered together. beta-Ionone was administered s.c. for 7 consecutive days and the P-450 activities were determined 3 days after the last administration. beta-Ionone induced cocaine N-demethylation, which is the first step in the activation of cocaine to the metabolites capable of producing hepatotoxicity, as well as P-450IA1- and P-450IIB1-specific monooxygenases. The inductive effects of beta-ionone on P-450IA1/2 and P-450IIB1/2 proteins were confirmed by using Western immunoblotting with selective monoclonal antibodies. In addition, when beta-ionone (600 mg/kg) was administered with cocaine for 7 days, the suppression of the antibody response was potentiated greatly, thymus weight was decreased significantly and serum glutamate-pyruvate transaminase was elevated. Our present results suggest that inhibition of the esterase pathway of cocaine shunts the metabolism of cocaine into an immunotoxic pathway, and that the metabolism of cocaine by P-450 may be the critical pathway for the generation of the metabolites capable of suppressing the antibody response.

Topics: Animals; Antibody Formation; Chemical and Drug Induced Liver Injury; Cocaine; Cytochrome P-450 Enzyme System; Diazinon; Enzyme Induction; Esterases; Female; Mice; Microsomes, Liver; Norisoprenoids; Terpenes