GENDER-RELATED DIFFERENCES IN SUSCEPTIBILITY TO ACETAMINOPHEN-INDUCEDPROTEIN ARYLATION AND NEPHROTOXICITY IN THE CD-1 MOUSE

Acetaminophen (APAP) is a commonly used analgesic and antipyretic agen t which, in high doses, causes liver and kidney necrosis in man and an imals. Damage in both target organs is greatly dependent upon biotrans formation. However, in the CD-1 mouse only males exhibit cytochrome P4 50-dependent nephrotoxicity and selective protein covalent binding. Th e lack of renal toxicity in female mice may reflect the androgen depen dence of renal CYP2EI. To study this, female mice were pretreated with testosterone propionate and then challenged 6 days later with APAP. G roups of control males and females were similarly challenged with APAP for comparison. All groups exhibited hepatotoxicity after APAP with s imilar glutathione (GSH) depletion, covalent binding, centrilobular ne crosis, and elevation of plasma sorbitol dehydrogenase activity. By co ntrast, APAP-induced nephrotoxicity occurred only in males and in the females pretreated with testosterone. No nephrotoxicity was evident in APAP-challenged control females. The selective pattern of hepatic and renal protein arylation previously reported for male mice was similar ly observed in testosterone-pretreated female mice. Western blot analy sis of microsomes showed that testosterone increased renal CYP2E1 leve ls without altering hepatic CYP2EI. Testosterone pretreatment, in vivo , also resulted in increased activation of APAP in vitro in kidney mic rosomes with no effect on the in vitro activation of APAP in liver mic rosomes. These data suggest that APAP-mediated GSH depletion, covalent binding, and toxicity in the kidneys of testosterone-pretreated femal es results from increased APAP activation by the testosterone-induced renal CYP2E1. This further suggests that renal, rather than hepatic, b iotransformation of APAP to a toxic electrophile is central to APAP-in duced nephrotoxicity in the mouse. (C) 1995 Academic Press, Inc.