Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure
Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure
复制标题
DOI：
10.1093/toxsci/kfn136
复制
发表时间：
2008-10-01
影响因子：
3.8
通讯作者：
Hoyer, Patricia B.
中科院分区：
文献类型：
--
作者：
Keating, Aileen F.;Rajapaksa, Kathila S.;Hoyer, Patricia B.
雌性动物天生就有数量有限的原始卵泡。4-乙烯基环己烯二环氧化物(VCD)是4-乙烯基环己烯(VCH)经1，2-和7，8-4-乙烯基环己烯单环氧化物(VCM)环氧化生成的代谢物。VCD特异性地破坏啮齿动物卵巢中的小的腔前(原始和小的初级)卵泡。细胞色素P450异构体2E1(细胞色素P450亚型2E1)I相酶参与了VCM向VCD的卵巢代谢。此外，微粒体环氧化物水解酶(Meh)可以将VCD解毒为无活性的四氢呋喃(4-(1，2-二羟基)乙基-1，2-二羟基环己烷)。本研究采用出生后第4天的小鼠全卵巢培养系统，研究了VCD诱导的卵毒性对129S(1)/SvImJ背景株小鼠(129S(1)/SvImJ)MEH的影响。本研究的假设是，在小鼠卵巢中，细胞色素P450-2基因的表达与meh基因的表达有关。与对照组相比，VCD暴露导致两种基因型的卵巢卵泡丢失(p<；0.05)；然而，15天后，这种损失在CYP2E1+/+卵巢中更大(p<；0.05)。在一段时间内(2-15天)，VCD(5亩M)可使卵巢组织中MeH基因的表达分别增加0.5倍(第10天)和1.84倍(第15天)，但对+/+卵巢无明显影响。7，12-二甲基苯并[a]菲(DMBA)也能破坏卵泡，但与VCD不同的是，DMBA被甲基甲烷激活为卵毒性的3，4-二醇-1，2-环氧化物代谢物。在增加DMBA浓度(0.5-1 mU M，15天)的情况下孵育卵巢，与+/+卵巢相比，CYP2E1-/-的卵泡丢失更多(p<；0.05)。随着mEH水平的提高(CYP2E1-/-)，DMBA引起的卵泡丢失增加(生物激活)，VCD引起的卵泡丢失减少(解毒)，支持卵巢中CYP2E1和mEH的表达可能存在关联。
Females are born with a finite number of primordial follicles. 4-Vinylcyclohexene diepoxide (VCD) is a metabolite formed by epoxidation of 4-vinylcyclohexene (VCH) via its two monoepoxides 1,2-and 7,8-4-vinylcyclohexene monoepoxide (VCM). VCD specifically destroys small preantral (primordial and small primary) follicles in the rodent ovary. The phase I enzyme, cytochrome P450 isoform 2E1 (CYP2E1) is involved in ovarian metabolism of VCM to VCD. Further, microsomal epoxide hydrolase (mEH) can detoxify VCD to an inactive tetrol (4-(1,2dihydroxy) ethyl-1,2-dihydroxycyclohexane). This study evaluated the effects of VCD-induced ovotoxicity on mEH in CYP2E1+/+ and -/-mice (129S(1)/SvImJ background strain) using a postnatal day 4 mouse whole ovary culture system. The hypothesis of our study is that there is a relationship between CYP2E1 and mEH gene expression in the mouse ovary. Relative to control, VCD exposure caused follicle loss (p < 0.05) in ovaries from both genotypes; however, after 15 days, this loss was greater (p < 0.05) in CYP2E1+/+ ovaries. In a time course (2-15 days), relative to control, VCD (5 mu M) caused an increase (p < 0.05) in mEH mRNA by 0.5-fold (day 10) and 1.84-fold (day 15) in CYP2E-/- but not +/+ ovaries. 7,12-Dimethylbenz[a] anthracene (DMBA) also destroys ovarian follicles but, unlike VCD, is bioactivated by mEH to an ovotoxic 3,4-diol-1,2-epoxide metabolite. Incubation of ovaries in increasing concentrations of DMBA (0.5-1 mu M, 15 days) resulted in greater (p < 0.05) follicle loss in CYP2E1-/-, relative to +/+ ovaries. With greater mEH (CYP2E1-/-), increased follicle loss with DMBA (bioactivation) and decreased follicle loss with VCD (detoxification) support that ovarian expression of CYP2E1 and mEH may be linked.