title: The effect of age on the glucuronidation and toxicity of 4,4'-thiobis(6-t-butyl-m-cresol).
abstract: Age-related changes in glucuronidation may potentially lead to a decrease in excretion of reactive compounds, resulting in enhanced toxic effects. 4,4'-Thiobis(6-t-butyl-m-cresol) (TBBC), a major antioxidant in the rubber industry, was selected as a model compound to evaluate glucuronidation as a function of age because it is directly conjugated to UDP-glucuronic acid (UDPGA) without requiring oxidative metabolism. To assess glucuronidation changes in vivo, male F344 rats, 2.5, 16, and 26 months of age, were administered 5 mg [14C]-TBBC/kg (10 microCi/kg) iv and urine and feces were collected for 3 days. Bile was also collected for 6 hr from animals of the same age groups after iv doses of 5 and 25 mg/kg [14C]TBBC. Total radioactivity was determined in all samples and the profile of metabolites in bile analyzed by HPLC. Along with a decrease in the older animal's ability to excrete TBBC-derived radioactivity in bile, feces, and urine, there was a decrease in the percentage of the dose eliminated in bile as glucuronide. In vitro, the microsomal glucuronyltransferase activity using TBBC as a substrate decreased in the senescent animals. The hepatic concentration of the cofactor UDPGA also decreased from 2.5 to 28 months of age. The apparent Vmax for the enzyme decreased as a function of age while the apparent Km decreased for the substrate (TBBC) but not for the cofactor (UDPGA) in the 26-month-old rats. These data suggest that with the decrease in the activity of the enzyme as well as a decrease in the available UDPGA, the ability of the senescent rats to conjugate and excrete TBBC may be altered. Thus, the in vitro decline in TBBC glucuronidation is compatible with the decreased excretion of TBBC-derived radioactivity observed in vivo in old rats. When toxicity was evaluated in 2.5-, 16-, and 26-month-old rats exposed to 0.25% TBBC in their diet for 14 days, no age-related change in the toxicity of TBBC was observed. However, there appeared to be an increase in leukemia in the treated senescent rats.
mesh_terms: D000367:Age Factors; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D003408:Cresols / Q000378:metabolism* / Q000633:toxicity; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000032:analysis; D007942:Leukemia, Experimental / Q000139:chemically induced; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis
chemical_list: D000975:Antioxidants; D003408:Cresols; D005965:Glucuronates; D014535:Uridine Diphosphate Glucuronic Acid; C040020:4,4'-thiobis(6-tert-butyl-3-cresol); D014453:Glucuronosyltransferase