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Madhu C, Gregus Z, Klaassen CD: Biliary excretion of acetaminophen-glutathione as an index of toxic activation of acetaminophen: effect of chemicals that alter acetaminophen hepatotoxicity. J Pharmacol Exp Ther. 1989 Mar;248(3):1069-77.
Acetaminophen (AA) is converted, presumably by cytochrome P-450, to an electrophile which is conjugated with glutathione (GS). AA-GS is excreted into bile, therefore the biliary excretion rate of AA-GS may reflect the rate of activation of AA in vivo. In order to test this hypothesis, the effect of agents capable of altering the activation of AA including cytochrome P-450 inducers and inhibitors, cobaltous chloride which decreases the amount of P-450, prostaglandin synthetase inhibitors (indomethacin and naproxen), antioxidants (butylated hydroxyanisole, alpha-tocopherol, ascorbic acid and ascorbic acid palmitate) and other chemicals known to decrease AA hepatotoxicity (dimethylsulfoxide and cysteamine), on the biliary excretion of AA-GS was studied in hamsters, the species most sensitive to AA-induced hepatotoxicity. The biliary excretion of AA-GS increased linearly up to 1 mmol/kg of AA i.v., but at higher dosages exhibited saturation kinetics. Dosages above 0.5 mmol/kg lowered hepatic GS concentration. Of the cytochrome P-450 inducers, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased the biliary excretion of AA-GS (2.9- and 3.2-fold, respectively) whereas ethanol and isoniazid did not affect it, and pregnenolone-16 alpha-carbonitrile tended to decrease it (43%). Phenobarbital tended to increase the biliary excretion of AA-GS, but not in a statistically significant manner. Several cytochrome P-450 inhibitors [metyrapone, 8-methoxypsoralen, 2-(4,6-dichloro-biphenyloxy) ethylamine, alpha-naphthoflavone and cimetidine] decreased the biliary excretion of AA-GS, although SKF 525-A and piperonyl butoxide did not. Cobaltous chloride decreased dramatically the biliary excretion of AA-GS.(ABSTRACT TRUNCATED AT 250 WORDS) |
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