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Background: 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.

Methods: 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.

Results: 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 noncanonical 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 Nacetyl 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.

Conclusion: 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.

Keywords: Sex differences, Cyp450, ROS, Cell death, Methylation


Originally published as: Penaloza, Carlos G., Mayra Cruz, Gabrielle Germain, Sidra Jabeen , Mohammad Javdan, Richard A. Lockshin, and Zahra Zaker. "Higher Sensitivity of Female Cells to Ethanol: Methylation of DNA Lowers Cyp2e1, Generating more ROS." Cell Communication and Signaling, vol. 18, no. 111, 2020,

© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.



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