Reference

Hepatotoxicity of butylated hydroxytoluene and its analogs in mice depleted of hepatic glutathione

Hepatotoxicity of butylated hydroxytoluene and its analogs in mice depleted of hepatic glutathione. Mizutani, Tamio; Nomura, Haruko; Nakanishi, Kazuo; Fujita, Setsuya (Dep. Food Sci., Kyoto Prefect. Univ., Kyoto 606, Japan). Toxicol. Appl. Pharmacol., 87(1), 166-76 (English) 1987. CODEN: TXAPA9. ISSN: 0041-008X. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) Mice treated with BHT (I) [128-37-0] (200-800 mg/kg, p.o.) in combination with an inhibitor of GSH [70-18-8] synthesis, buthionine sulfoximine (BSO; 1 h before and 2 h after BHT, 4 mmol/kg per dose, i.p.) developed hepatotoxicity characterized by an increase in serum GPT [9000-86-6] activity and centrilobular necrosis of hepatocytes. The hepatotoxic response was both time- and dose-dependent. BHT (￡800 mg/kg) alone produced no evidence of liver injury. As judged by the observation of normal serum GPT, drug metab. inhibitors such as SKF-525A, piperonyl butoxide, and CS2 prevented the hepatotoxic effect of BHT given in combination with BSO. On the other hand, pretreatment with cedar wood oil resulted in increased hepatic injury in mice treated with both BHT and BSO. Pretreatment with phenobarbital also tended to increase hepatic injury as judged by changes in serum GPT. Apparently, BHT is activated by a cytochrome-P 450-dependent metabolic reaction and the hepatotoxic effect is caused by inadequate rates of detoxification of the reactive metabolite in mice depleted of hepatic GSH by BSO administration. The hepatotoxic potencies of BHT-related compds.There are some commonly used reagents with their cas registry numbers 96-70-8 and 43109-72-4 in this article. also were examd. in BSO-treated animals. For hepatotoxicity, the phenolic ring must have benzylic H atoms at the 4 position and an ortho-alkyl group(s) that moderately hinders the hydroxyl group. These structural requirements essentially are the same as those for the toxic potency in the lung (T. Mizutani et al., 1982), and support the hypothesis that BHT-quinone methide plays a role in producing liver damage in mice with depressed hepatic GSH levels. .