Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic γ-glutamyltranspeptidase activity; hamsters and mice (low γ-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high γ-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively. Most of the detoxication pathway metabolites appeared in urine. Half of the detoxication pathway metabolites in rats was AA-sulfate, whereas the other species excreted mainly AA-glucuronide. The ratio of toxication/detoxication pathway metabolites excreted was 2.2, 1.0, 0.25, 0.1 and 0.08 for hamsters, mice, rabbits, rats and guinea pigs, respectively. These ratios are inversely related to the hepatotoxic dose reported for these species, indicating that sensitivity to AA-induced liver necrosis is determined by the balance between toxication and detoxication metabolic pathways.
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Jan 1 1988|
ASJC Scopus subject areas
- Molecular Medicine