Toxicity and Metabolism of Eugenol, a Food Additive

丁香酚被广泛用作食品调味剂和牙科止痛剂。丁香酚（400-600 mg/kg，po）联合谷胱甘肽（GSH）合成抑制剂丁硫酰亚胺（BSO ; 4 mmol/kg，ip）处理的小鼠出现肝毒性，其特征为相对肝脏重量和血清GPT增加、肝充血和肝细胞坏死。药物代谢抑制剂，如二硫化卡伯特和甲氧沙林防止丁香酚与BSO联合给药的肝毒性作用。这些结果表明，丁香酚是由细胞色素P-450依赖性代谢反应激活，肝损伤是由肝GSH耗竭小鼠中产生的代谢产物的解毒率不足引起的。研究了几种丁香酚类似物如黄樟素和chavibetol在GSH耗竭小鼠中引起肝损伤的能力。比较;测试化合物的Wrison表明，毒性效力的结构要求是在4位具有烯丙基取代基的酚环。这些结构。可以通过假设通过丁香酚的代谢氧化而调节的乙烯基苯醌甲基化物在诱导肝毒性中起作用来解释这些要求。

Eugenol is widely used as a food flavoring agent and a dental analgesic. Mice treated with eugenol(400-600 mg/kg, po)in combination with an inhibitor of glutathione(GSH)synthesis, buthionine sufoximine(BSO ; 4 mmol/kg, ip)developed hepatotoxicity characterized by increases in relative liver weight and serum GPT, hepatic congestion, and necrosis of hepatocytes. Drug metabolism inhibitors such as carbort disulfide and methoxsalen prevented the hepatotoxic effect of eugenol given in combination with BSO. These results suggest that eugenol is activated by a cytochrome-P-450-dependent metabolic reaction and that the liver injury is caused by inadequate rates of detoxification of the resulting metabolite in mice depleted of hepatic GSH. Several eugenol analogs such as safrole and chavibetol were examinedfor their ability to cause hepatic injury in GSH-depleted mice. Comp ; Wrison of the tested compounds showed that the structural requirements for toxic potency was a phenolic ring having an allyl substituent at the 4-position. These structural. requirements can be explained by assuming that a vinylogous quinone methide tonned by metabolic oxidation of eugenol plays a role in inducing hepatotoxicity.