SEX-DEPENDENT AND AGE-DEPENDENT ACETAMINOPHEN HEPATOTOXICITY AND NEPHROTOXICITY IN SPRAGUE-DAWLEY RATS - ROLE OF TISSUE ACCUMULATION, NONPROTEIN SULFHYDRYL DEPLETION, AND COVALENT BINDING

Acetaminophen (APAP) produces sex-dependent nephrotoxicity and hepatot oxicity in young adult Sprague-Dawley (SD) rats and age-dependent toxi city in male rats, There is no information regarding the susceptibilit y of aging female SD rats to APAP toxicity, Therefore, the present stu dies were designed to determine if sex-dependent differences in APAP t oxicity persist in aging rats and to elucidate factors contributing to sex- and age-dependent APAP hepatotoxicity and nephrotoxicity, Young adult (3 months old) and aging (18 months old) male and female rats we re killed from 2 through 24 hr after receiving APAP (0-1250 mg/kg, ip) containing [ring-C-14]APAP, Trunk blood was collected for determinati on of blood urea nitrogen (BUN) concentration, serum alanine aminotran sferase (ALT) activity, and plasma APAP concentration; urine was colle cted for determination of glucose and protein excretion; and liver and kidneys were removed for determination of tissue glutathione (GSH) co ncentration, APAP concentration, and covalent binding, APAP at 1250 mg /kg induced nephrotoxicity (as indicated by elevations in BUN concentr ation) in 3-month-old females but not males, whereas APAP induced hepa totoxicity (as indicated by elevations in serum ALT activity) in 3-mon th-old males but not females, Sex differences in APAP toxicity were no longer apparent in 18-month-old rats. APAP at 750 mg/kg ip produced l iver and kidney damage in 18-month-old but not 3-month-old male and fe male rats. No consistent sex- or age-dependent differences in serum, h epatic, and renal APAP concentrations were observed that would account for differences in APAP toxicity. No sex- or age-dependent difference s in tissue GSH depletion or covalent binding of radiolabel from APAP in livers or kidneys were observed following APAP administration, Util izing an affinity-purified polyclonal antibody raised against APAP, ar ylated proteins with electrophoretic mobility similar to those observe d in mice were prominent in rat livers following APAP administration t o 3- and 18-month-old rats of both sexes, In contrast, no arylated pro teins were detected in any rat kidneys following APAP administration, Absence of immunochemically detectable proteins in rat kidney followin g APAP administration is in direct contrast to observations in mice an d supports the hypothesis that mechanisms of APAP hepatotoxicity and n ephrotoxicity in rats and mice are distinctly different. In conclusion , sex differences in APAP toxicity are observed only in young adult (3 -month-old) rats and sex differences are organ-specific with males mor e susceptible to hepatotoxicity and females more susceptible to nephro toxicity, Aging rats are more susceptible to APAP-induced damage to bo th the liver and the kidney than are 3-month-old rats but sex differen ces are no longer apparent in 18-month-old rats, The mechanisms contri buting to sex- and age-dependent differences in APAP toxicity cannot b e attributed to differences in tissue APAP concentrations, GSH depleti on, or covalent binding. (C) 1996 Society of Toxicology