Higher sensitivity of female cells to ethanol: methylation of DNA lowers Cyp2e1, generating more ROS.

Autor: Penaloza CG; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA.; Present Address: Chancellor's Office, Leeward Community College, Pearl City, HI, USA., Cruz M; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA., Germain G; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA., Jabeen S; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA., Javdan M; Queensborough Community College, City College of New York, Bayside, NY, USA., Lockshin RA; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA., Zakeri Z; Queens College and Graduate Center, City University of New York, 65-30 Kissena Blvd, NSB E143, Flushing, NY, 11367, USA. Zahra_zakeri@hotmail.com.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2020 Jul 11; Vol. 18 (1), pp. 111. Date of Electronic Publication: 2020 Jul 11.
DOI: 10.1186/s12964-020-00616-8
Abstrakt: 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 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.
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.
Databáze: MEDLINE
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