METABOLISM OF TERT-BUTYLHYDROQUINONE TO S-SUBSTITUTED CONJUGATES IN THE MALE FISCHER-344 RAT

tert-Butyl-4-hydroxyanisole (BHA) and its demethylated analog, tert-bu tyl-hydroquinone (TBHQ), are antioxidants used in food. Both BHA and T BHQ have been shown to promote kidney and bladder carcinogenesis in th e rat. We have previously demonstrated that glutathione (GSH) conjugat es of a variety of hydroquinones are nephrotoxic and proposed that GSH conjugation serves to target these compounds to the kidney. In the pr esent study, we examined the metabolism of TBHQ, focusing on the forma tion of potentially nephrotoxic sulfur-containing metabolites. 2-tert- Butyl-5-glutathion-S-ylhydroquinone, 2-tert-butyl-6-glutathion-S-ylhyd roquinone, and 2-tert-butyl-3,6-bisglutathion-S-ylhydroquinone were id entified as biliary metabolites of TBHQ (1.0 mmol/kg, ip) in male F344 rats, accounting for 2.2% of the dose. Liquid chromatography/mass spe ctroscopic analysis of urine also revealed the presence of additional sulfur-containing metabolites, tentatively identified as 2,5-dihydroxy -3-tert-butylthiophenol, 2,5-dihydroxy-4-tert-butylthiophenol, and the ir S-methyl derivatives. No mercapturic acids of TBHQ were found in th e urine. The major biliary and urinary metabolites were TBHQ-glucuroni de and TBHQ-sulfate, with a trace of TBHQ excreted unchanged. The resu lts indicate that TBHQ undergoes oxidation and GSH conjugation in vivo in the male F344 rat. These conjugates are excreted into bile and und ergo further metabolism prior to excretion in urine. Formation of the S-containing metabolites of TBHQ may occur in amounts sufficient to pl ay a role in the toxicity of TBHQ to kidney and bladder.