title: Intrinsic susceptibility of the kidney to acetaminophen toxicity in middle-aged rats.
abstract: Acetaminophen (APAP)-induced nephrotoxicity is age-dependent in male Sprague-Dawley (SD) rats: middle-aged (9-12 months old) rats exhibit nephrotoxicity at lower dosages of APAP than do young adults (2-3 months old). The present study was designed to test the hypothesis that the intrinsic susceptibility of renal tissue to APAP toxicity is increased in middle-aged rats. APAP toxicity was evaluated in renal slices from naive 3- and 12-month-old male SD rats incubated with 0-50 mM APAP for 2-8 h. Renal slice glutathione (GSH) and APAP concentrations were determined; renal function was assessed by organic anion (para-aminohippurate, PAH) and cation (tetraethylammonium, TEA) accumulation; and cell viability was assessed by lactate dehydrogenase (LDH) leakage. At each concentration of APAP tested, accumulation of APAP by renal slices was similar in 3- and 12-month-olds. APAP toxicity in renal slices from both 3- and 12-month-old rats was characterized by concentration-dependent increases in LDH leakage. In contrast to APAP nephrotoxicity in vivo, APAP toxicity in renal slices was accompanied by decreased accumulation of PAH and TEA. Additionally, APAP produced marked reductions in renal slice GSH content in a concentration-dependent manner: however, in contrast to APAP nephrotoxicity in vivo, APAP-induced GSH depletion in vitro did not precede cytotoxicity. No consistent age-dependent differences in the time- and concentration-response curves for APAP nephrotoxicity were observed. These data suggest that APAP cytotoxicity in vitro is not increased in 12-month-old rats. However, since the pattern (and mechanisms) of APAP cytotoxicity in vitro appears to be different from that observed in vivo, extrapolation of in vitro cytotoxicity to in vivo nephrotoxicity is limited. Therefore, age differences in intrinsic susceptibility of the intact kidney cannot be excluded as a mechanism contributing to enhanced APAP nephrotoxicity in middle-aged rats.
authors.affiliation: Department of Investigative Toxicology, Smith Kline & French Laboratories, King of Prussia, PA.
authors.forename: J B
authors.initials: JB
authors.lastname: Tarloff
authors.forename: R S
authors.initials: RS
authors.lastname: Goldstein
authors.forename: A C
authors.initials: AC
authors.lastname: Silver
authors.forename: W R
authors.initials: WR
authors.lastname: Hewitt
authors.forename: J B
authors.initials: JB
authors.lastname: Hook
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000375:Aging / Q000502:physiology*; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D013757:Tetraethylammonium Compounds; D000082:Acetaminophen; D005978:Glutathione; D010130:p-Aminohippuric Acid