Department of Biochemistry, V. P. Chest Institute, University of Delhi, Delhi, 110007, India.
Arch Toxicol. 2011 Sep;85(9):1141-50. doi: 10.1007/s00204-011-0646-9. Epub 2011 Jan 26.
Previous investigations carried out in our laboratory have highlighted that 7,8-diacetoxy-4-methylcoumarin demonstrates a mechanism-based inhibition of cytochrome P450 (Cyt-P450) activities such as microsome-mediated aflatoxin B1 (AFB1) epoxidation, dealkylation of alkylated resorufin, and toxicokinetics of benzene. 7,8-Diacetoxy-4-methylcoumarin, quercetin pentaacetate, and ellagic acid peracetate were also found to be effective in giving the protection of AFB1-induced genotoxicity in rat's bone marrow and lung cells possibly due to acetylation of Cyt-P450 apoprotein mediated by acetoxy drug: protein transacetylase. Later, this transacetylase was identified as calreticulin, and the acetyltransferase function of calreticulin was appropriately termed calreticulin transacetylase. In this communication, we have focused on the superiority of several classes of polyphenolic acetates to polyphenols in the modification of Cyt-P450-linked mixed function oxidases (MFOs) such as 7-ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD). Special attention has also been focused on benzene-induced genotoxicity in bone marrow and lung cells. Results clearly indicated that polyphenolic acetates demonstrated time-dependent inhibition of Cyt-P450-linked MFOs, while parent polyphenols failed to demonstrate the same. Polyphenolic acetates were found to be more superior to polyphenols in preventing benzene-induced micronuclei formation. The pattern of inhibition of Cyt-P450-dependent MFOs and benzene-induced micronuclei formation by polyphenolic acetates was found in tune with their specificities to calreticulin transacetylase. These results further substantiated that inhibition of Cyt-P450-linked MFOs and benzene-induced genotoxicity in bone marrow and lung cells by polyphenolic acetates are mediated by the action of calreticulin transacetylase that catalyzes the acetylation of concerned proteins.
先前在我们实验室进行的研究表明，7,8-二乙酰氧基-4-甲基香豆素对细胞色素 P450（Cyt-P450）活性具有机制性抑制作用，如微粒体介导的黄曲霉毒素 B1（AFB1）环氧化、烷基化的荧光素脱烷基化以及苯的毒代动力学。还发现 7,8-二乙酰氧基-4-甲基香豆素、槲皮素五乙酸酯和鞣花酸五乙酸酯可有效保护 AFB1 诱导的大鼠骨髓和肺细胞的遗传毒性，这可能是由于细胞色素 P450 脱辅基蛋白的乙酰化由乙酰氧基药物：蛋白转乙酰基酶介导。后来，这种转乙酰基酶被鉴定为钙网蛋白，钙网蛋白的乙酰转移酶功能被恰当地命名为钙网蛋白转乙酰基酶。在本通讯中，我们专注于几类多酚乙酸酯类物质在修饰细胞色素 P450 相关混合功能氧化酶（MFO）方面的优势，如 7-乙氧基荧光素 O-去乙基酶（EROD）和戊氧基荧光素 O-脱烷基酶（PROD）。特别关注的是苯诱导的骨髓和肺细胞遗传毒性。结果清楚地表明，多酚乙酸酯类物质对细胞色素 P450 相关 MFO 具有时间依赖性抑制作用，而母体多酚则未能表现出相同的作用。多酚乙酸酯类物质在预防苯诱导的微核形成方面比多酚类物质更具优势。多酚乙酸酯类物质对细胞色素 P450 依赖性 MFO 的抑制作用和苯诱导的微核形成模式与它们对钙网蛋白转乙酰基酶的特异性一致。这些结果进一步证实，多酚乙酸酯类物质对细胞色素 P450 相关 MFO 的抑制作用和苯诱导的骨髓和肺细胞遗传毒性是通过钙网蛋白转乙酰基酶的作用介导的，该酶催化相关蛋白的乙酰化。
