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Higher sensitivity of female cells to ethanol: methylation of DNA lowers Cyp2e1, generating more ROS.
Cell Communication and Signaling ( IF 8.2 ) Pub Date : 2020-07-11 , DOI: 10.1186/s12964-020-00616-8
Carlos G Penaloza 1, 2 , Mayra Cruz 1 , Gabrielle Germain 1 , Sidra Jabeen 1 , Mohammad Javdan 3 , Richard A Lockshin 1 , Zahra Zakeri 1
Affiliation  

Cells taken from mouse embryos before sex differentiation respond to insults according to their chromosomal sex, a difference traceable to differential methylation. We evaluated the mechanism for this difference in the controlled situation of their response to ethanol. We evaluated the expression of mRNA for alcohol dehydrogenase (ADH), aldehyde dehyrogenases (ALDH), and a cytochrome P450 isoenzyme (Cyp2e1) in male and female mice, comparing the expressions to toxicity under several experimental conditions evaluating redox and other states. Females are more sensitive to ethanol. Disulfiram, which inhibits alcohol dehydrogenase (ADH), increases cell death in males, eliminating the sex dimorphism. The expressions ADH Class 1 to 4 and ALDH Class 1 and 2 do not differ by sex. However, females express approximately 8X more message for Cyp2e1, an enzyme in the non-canonical pathway. Female cells produce approximately 15% more ROS (reactive oxygen species) than male cells, but male cells contain approximately double the concentration of GSH, a ROS scavenger. Scavenging ROS with N-acetyl cysteine reduces cell death and eliminates sex dimorphism. Finally, since many of the differences in gene expression derive from methylation of DNA, we exposed cells to the methyltransferase inhibitor 5-aza- 2-deoxycytidine; blocking methylation eliminates both the difference in expression of Cyp2e1 and cell death. We conclude that the sex-differential cell death caused by ethanol derives from sex dimorphic methylation of Cyp2e1 gene, resulting in generation of more ROS.

中文翻译:

雌性细胞对乙醇的敏感性更高:DNA 甲基化降低 Cyp2e1,产生更多 ROS。

在性别分化之前取自小鼠胚胎的细胞根据其染色体性别对损伤做出反应,这种差异可追溯到差异甲基化。我们评估了他们对乙醇反应的受控情况下这种差异的机制。我们评估了雄性和雌性小鼠中乙醇脱氢酶 (ADH)、醛脱氢酶 (ALDH) 和细胞色素 P450 同工酶 (Cyp2e1) 的 mRNA 表达,比较了几种评估氧化还原和其他状态的实验条件下的毒性表达。女性对乙醇更敏感。双硫仑可抑制酒精脱氢酶 (ADH),增加男性细胞死亡,消除性别二态性。ADH Class 1 到 4 和 ALDH Class 1 和 2 的表达方式没有性别差异。然而,对于 Cyp2e1,女性表达的信息大约多 8 倍,非经典途径中的一种酶。雌性细胞产生的 ROS(活性氧物质)比雄性细胞多约 15%,但雄性细胞中的 GSH 浓度约为 ROS 清除剂的两倍。用 N-乙酰半胱氨酸清除 ROS 可减少细胞死亡并消除性别二态性。最后,由于基因表达的许多差异源于 DNA 的甲基化,我们将细胞暴露于甲基转移酶抑制剂 5-aza-2-deoxycytidine;阻断甲基化消除了 Cyp2e1 表达的差异和细胞死亡。我们得出结论,乙醇引起的性别差异细胞死亡源于 Cyp2e1 基因的性别二态甲基化,导致产生更多的 ROS。但雄性细胞含有大约两倍浓度的 GSH,一种 ROS 清除剂。用 N-乙酰半胱氨酸清除 ROS 可减少细胞死亡并消除性别二态性。最后,由于基因表达的许多差异源于 DNA 的甲基化,我们将细胞暴露于甲基转移酶抑制剂 5-aza-2-deoxycytidine;阻断甲基化消除了 Cyp2e1 表达的差异和细胞死亡。我们得出结论,乙醇引起的性别差异细胞死亡源于 Cyp2e1 基因的性别二态甲基化,导致产生更多的 ROS。但雄性细胞含有大约两倍浓度的 GSH,一种 ROS 清除剂。用 N-乙酰半胱氨酸清除 ROS 可减少细胞死亡并消除性别二态性。最后,由于基因表达的许多差异源于 DNA 的甲基化,我们将细胞暴露于甲基转移酶抑制剂 5-aza-2-deoxycytidine;阻断甲基化消除了 Cyp2e1 表达的差异和细胞死亡。我们得出结论,乙醇引起的性别差异细胞死亡源于 Cyp2e1 基因的性别二态甲基化,导致产生更多的 ROS。我们将细胞暴露于甲基转移酶抑制剂 5-aza-2-deoxycytidine;阻断甲基化消除了 Cyp2e1 表达的差异和细胞死亡。我们得出结论,乙醇引起的性别差异细胞死亡源于 Cyp2e1 基因的性别二态甲基化,导致产生更多的 ROS。我们将细胞暴露于甲基转移酶抑制剂 5-aza-2-deoxycytidine;阻断甲基化消除了 Cyp2e1 表达的差异和细胞死亡。我们得出结论,乙醇引起的性别差异细胞死亡源于 Cyp2e1 基因的性别二态甲基化,导致产生更多的 ROS。
更新日期:2020-07-13
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