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Protective Role of CYP 2E1 Inhibitor Diallyl Disulfide ( DADS ) on Alcohol‐Induced Malondialdehyde‐Deoxyguanosine (M1dG) Adduct Formation
Author(s) -
Sapkota Muna,
Hottor Tete K.,
DeVasure Jane M.,
Wyatt Todd A.,
McCaskill Michael L.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12439
Subject(s) - malondialdehyde , chemistry , cyp2e1 , lipid peroxidation , diallyl disulfide , deoxyguanosine , oxidative stress , biochemistry , pharmacology , reactive oxygen species , cytochrome p450 , medicine , metabolism , apoptosis
Background Alcohol use disorders are often associated with lung disease. Alcohol exposure leads to the production of reactive oxygen species, lipid peroxidation, and formation of malondialdehyde ( MDA ) as well as to induce the expression of cytochrome p450 2E1 ( CYP 2E1). Likewise, cigarette smoking can lead to lung lipid peroxidation and formation of MDA . MDA can bind to DNA forming MDA ‐deoxyguanosine (M1dG) adducts, which have been implicated in alcohol‐related cancers and cardiovascular disease. Because CYP 2E1 regulates MDA production, and our previous studies have shown that alcohol and cigarette smoke can lead to MDA formation, we hypothesized that CYP 2E1 would modulate M1dG adduct formation and single‐strand DNA damage in alcohol‐ and cigarette smoke‐exposed lung cells and tissue. Methods Normal human bronchial epithelial cells (HBECs) were pretreated with 10 μ M diallyl disulfide ( DADS ) for 1 hour and treated with 80 mM ethanol (EtOH) ± 5% cigarette smoke extract (CSE) for 3 hours for comet assay and 6 hours for CYP2E1, MDA, and M1dG adduct assays. C57BL/6 mice were administered 20% EtOH ad libitum in drinking water for 8 weeks and exposed to whole‐body cigarette smoke for 5 weeks. Mice were also fed a CYP2E1 inhibitor, DADS, at 1 μ M/g of feed in their daily diet for 7 weeks. Whole lung tissue homogenate was used for CYP2E1, MDA , and M1dG adduct assays. Results EtOH exposure significantly increased HBEC olive tail moment. DADS pretreatment of HBEC s attenuated this EtOH effect. EtOH also induced MDA and M1dG adduct formation, which was also significantly reduced by DADS treatment. CSE ± EtOH did not enhance these effects. In lung tissue homogenate of 8‐week alcohol‐fed mice, MDA and M1dG adduct levels were significantly elevated in comparison with control mice and mice fed DADS while consuming alcohol. No increase in MDA and M1dG adduct formation was observed in 5‐week cigarette smoke‐exposed mice. Conclusions These findings suggest that CYP 2E1 plays a pivotal role in alcohol‐induced M1dG adducts, and the use of DADS as dietary supplement can reverse the effects of alcohol on M1dG formation.