Toxicity and Metabolism of Eugenol, a Food Additive

食品添加剂丁子香酚的毒性和代谢

• 批准号: 02680068
• 负责人: MIZUTANI Tamio
• 金额: $ 1.22万
• 依托单位: Kyoto Prefectural University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02680068/
• 关键词: Buthionine sulfoximine; Eugenol; Glutathione; Hepatotoxicity; Metabolic activation; Mouse

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.

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。

项目成果

Tamio Mizutani: "Hepatotoxicity of Eugenol in Mice Depleted of Glutathione by Treatment with DLーButhionine Sulfoximine" Res.Commun.Chem.Pathol.Pharmacol.71. 219-230 (1991)

Tamio Mizutani：“用 DL-丁硫氨酸磺胺治疗后，丁香酚对谷胱甘肽耗尽的小鼠的肝毒性”Res.Commun.Chem.Pathol.Pharmacol.71 (1991)。

Tamio Mizutani: "hepatotoxicity of Eugenol in Mice Depleted of Glutathione by Treatement with DL-Buthionine Sulfoximine" Res.Commun.Chem.Pathol.Pharmacol.71. 219-230 (1991)

Tamio Mizutani：“用 DL-丁硫氨酸亚磺酰亚胺治疗后，丁子香酚对谷胱甘肽耗尽的小鼠的肝毒性”Res.Commun.Chem.Pathol.Pharmacol.71。

T. Mizutani, K. Satoh, H. Nomura and K. Nakanishi: "Hepatotoxicity of Eugenol in Mice Depleted of Glutathione by Treatment with DL-Buthionine Sulfoximine." Res. Commun. Chem. Pathol. Pharmacol.71 (2). 219-230 (1991)

T. Mizutani、K. Satoh、H. Nomura 和 K. Nakanishi：“用 DL-丁硫氨酸磺胺亚胺治疗耗尽谷胱甘肽的小鼠中丁子香酚的肝毒性”。

Tamio Mizutani: "Hepatotoxicity of Eugenol in Mice Depleted of Glutathione by Treatment with DLーButhionine Sulfoximine" Res.Commun.Chem.Pathol.Pharmacol.71. (1991)

Tamio Mizutani：“用 DL-丁硫氨酸磺胺治疗后，丁香酚对谷胱甘肽耗尽的小鼠的肝毒性”Res.Commun.Chem.Pathol.Pharmacol.71 (1991)。

Tamio Mizutani: "Hepatotoxicity of Eugenol and Related Compounds in Mice Depleted of Glutathione:Structural Requirements for Toxic Potency" Res.Commun.Chem.Pathol.Pharmacol.73. 87-95 (1991)

Tamio Mizutani：“谷胱甘肽耗尽小鼠中丁子香酚和相关化合物的肝毒性：毒性效力的结构要求”Res.Commun.Chem.Pathol.Pharmacol.73。