Contribution of oxidation and deacetylation to the bioactivation of acetaminophen in vitro in liver and kidney from male and female Sprague-Dawley rats.
Young adult female Sprague-Dawley (SD) rats are more susceptible to acetaminophen (APAP)-induced nephrotoxicity than are age-matched male SD rats. Mechanisms contributing to sex-dependent APAP nephrotoxicity may involve differences in APAP bioactivation via cytochrome P450-dependent metabolism to N-acetyl-p-benzoquinoneimine and/or deacetylation to para-amino-phenol. APAP bioactivation by oxidation and deacetylation was assessed by examining the effects of 1-aminobenzotriazole (ABT), a suicide substrate inhibitor of cytochrome P450, and bis-(para-nitrophenyl) phosphate (BNPP), a reversible carboxyesterase inhibitor, on covalent binding of APAP-derived radiolabel. Hepatic and renal S9 fractions prepared from naive male and female rats were incubated with [14C-ring]-APAP in the presence and absence of NADPH. There were no sex-related differences in covalent binding of APAP-derived radiolabel in hepatic or renal S9 fractions from male and female rats. In both sexes, incubation of hepatic or renal S9 fractions with 10 mM ABT significantly reduced covalent binding of APAP-derived radiolabel as compared with covalent binding in the absence of ABT. In contrast, incubation of renal and hepatic S9 fractions with 10 mM BNPP did not alter covalent binding of radiolabel derived from APAP in either males or females. Thus, at least in vitro, differences in bioactivation of APAP in liver and kidney from male and female SD rats do not seem to contribute to sex-dependent APAP toxicity. Carboxyesterases inhibited by BNPP do not seem to contribute to covalent binding of APAP-derived radiolabel in vitro in either liver or kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Mugford
C A
CA
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, PA 19104-4495.
Tarloff
J B
JB
D000082:Acetaminophen / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005260:Female; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced; D008099:Liver / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D014230:Triazoles / Q000494:pharmacology
D002250:Carbon Radioisotopes; D009596:Nitrophenols; D014230:Triazoles; C033020:1-aminobenzotriazole; D000082:Acetaminophen; C002887:bis(4-nitrophenyl)phosphate