Raj H G, Malik S, Parmar V S, Kohli E, Tyagi Y K, Rohil V, Dwarakanath B S, Adhikari J S, Bose M, Jain S C, Olsen C E
V.P. Chest Institute, University of Delhi, P.O. Box 2101, Delhi-110007, India.
Teratog Carcinog Mutagen. 2001;21(2):181-7.
Our earlier studies documented the ability of 7,8-diacetoxy-4-methylcoumarin (DAMC) to cause irreversible inhibition of cytochrome P-450 linked mixed function oxidases (MFO) mediated by membrane bound DAMC: protein transacetylase. Since P-450 catalyzed oxidation of benzene is crucial to its toxic effects, the action of DAMC and related analogues were considered promising in preventing the genotoxicity due to benzene. For this purpose rats were pretreated with various acetoxy-4-methylcoumarins (test compounds), which was followed by the administration of benzene either intratracheally (IT) or intraperitoneally (IP), and sacrificed 26 h after the injection of benzene. The incidence of micronuclei (MN) in bone marrow (BM) and lung (LG) were assessed by light and fluorescent microscopy, respectively. A dose-dependent induction of MN in BM and LG cells was observed in rats administered with benzene. A significant reduction in benzene-induced MN in BM and LG was observed as a result of DAMC administration to rats; a higher dose of DAMC resulted in greater inhibition of clastogenic action of benzene as revealed by MN incidence. 7,8-dihydroxy-4-methylcoumarin (DHMC), the deacetylated product of DAMC, demonstrated relatively lesser potency to inhibit the clastogenic action of benzene. This observation is consistent with the ability of DAMC to inhibit the formation of benzene oxide as well as to scavenge the oxygen radicals formed during the course of benzene metabolism. The fact that DHMC can only scavenge the oxygen radicals and is ineffective in inhibiting benzene oxidation in vivo explains the reduced capability of dihydroxy coumarin to prevent MN due to benzene. 7-Acetoxy-4-methylcoumarin (MAC) inhibits the MN due to benzene being roughly 50% of that produced by DAMC. DAMC is also effective in normalizing the cell cycle alterations produced by benzene in BM and LG. These observations further substantiate our hypothesis that the biological effects of acetoxy coumarins are mediated by the action of membrane bound transacetylase that catalyzes the acetylation of concerned proteins. Teratogenesis Carcinog. Mutagen. 21:181-187, 2001.
我们早期的研究记录了7,8 - 二乙酰氧基 - 4 - 甲基香豆素（DAMC）能够不可逆地抑制由膜结合的DAMC：蛋白质转乙酰酶介导的细胞色素P - 450相关的混合功能氧化酶（MFO）。由于P - 450催化的苯氧化对其毒性作用至关重要，因此DAMC及其相关类似物的作用被认为在预防苯引起的遗传毒性方面很有前景。为此，用各种乙酰氧基 - 4 - 甲基香豆素（测试化合物）对大鼠进行预处理，随后通过气管内（IT）或腹腔内（IP）给予苯，并在注射苯后26小时处死大鼠。分别通过光学显微镜和荧光显微镜评估骨髓（BM）和肺（LG）中的微核（MN）发生率。在用苯处理的大鼠中，观察到BM和LG细胞中MN呈剂量依赖性诱导。给大鼠施用DAMC后，观察到BM和LG中苯诱导的MN显著减少；较高剂量的DAMC导致对苯的致断裂作用的抑制作用更强，这通过MN发生率得以体现。7,8 - 二羟基 - 4 - 甲基香豆素（DHMC）是DAMC的脱乙酰产物，其抑制苯致断裂作用的效力相对较小。这一观察结果与DAMC抑制苯氧化物形成以及清除苯代谢过程中形成的氧自由基的能力一致。DHMC只能清除氧自由基且在体内抑制苯氧化无效这一事实解释了二羟基香豆素预防苯诱导的MN的能力降低。7 - 乙酰氧基 - 4 - 甲基香豆素（MAC）对苯诱导的MN的抑制作用约为DAMC产生的抑制作用的50％。DAMC在使苯在BM和LG中产生的细胞周期改变正常化方面也有效。这些观察结果进一步证实了我们的假设，即乙酰氧基香豆素的生物学效应是由催化相关蛋白质乙酰化的膜结合转乙酰酶的作用介导的。《致畸、致癌、致突变》2001年第21卷第181 - 187页
