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)合成抑制剂丁硫氨酸亚胺(BSO；4 mmol/kg，ip)可引起小鼠肝毒性，表现为肝相对重量和血清GPT升高、肝充血和肝细胞坏死。药物代谢抑制剂，如碳水化合物、二硫化物和甲氧沙林，可预防丁香酚与BSO联合给药的肝毒性作用。这些结果表明，丁香酚是由依赖细胞色素-P-450的代谢反应激活的，肝脏损伤是由于肝脏GSH耗竭的小鼠所产生的代谢物解毒率不足所致。研究了几种丁香酚类似物，如黄樟素和查维倍他醇对谷胱甘肽耗竭小鼠肝损伤的影响。受试化合物的比较表明，毒性的结构要求是在4-位具有烯丙基取代基的酚环。这些是结构性的。需求可以通过假设丁香酚的代谢氧化调色的乙烯基喹酮甲基化合物在诱导肝脏毒性中起作用来解释。

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.