Protective Role of CYP2E1 Inhibitor diallyl disulfide (DADS) on Alcohol-induced malondialdehyde-deoxyguanosine (M1dG) adduct formation

Muna Sapkota, Tete K. Hottor, Jane M. Devasure, Todd A Wyatt, Michael L. Mccaskill

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 (CYP2E1). 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 CYP2E1 regulates MDA production, and our previous studies have shown that alcohol and cigarette smoke can lead to MDA formation, we hypothesized that CYP2E1 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 μM 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 μM/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 HBECs 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 CYP2E1 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.

Original languageEnglish (US)
Pages (from-to)1550-1558
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume38
Issue number6
DOIs
StatePublished - Jun 2014

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Cytochrome P-450 CYP2E1
Deoxyguanosine
Malondialdehyde
Alcohols
Tobacco Products
Smoke
Assays
Lung
Epithelial Cells
Tissue
Lipid Peroxidation
diallyl disulfide
Dietary supplements
Lipids
Pulmonary diseases
Comet Assay
DNA
Olea
Nutrition
Dietary Supplements

Keywords

  • CYP2E1
  • DADS
  • EtOH
  • M1dG
  • Malondialdehyde

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Protective Role of CYP2E1 Inhibitor diallyl disulfide (DADS) on Alcohol-induced malondialdehyde-deoxyguanosine (M1dG) adduct formation. / Sapkota, Muna; Hottor, Tete K.; Devasure, Jane M.; Wyatt, Todd A; Mccaskill, Michael L.

In: Alcoholism: Clinical and Experimental Research, Vol. 38, No. 6, 06.2014, p. 1550-1558.

Research output: Contribution to journalArticle

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abstract = "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 (CYP2E1). 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 CYP2E1 regulates MDA production, and our previous studies have shown that alcohol and cigarette smoke can lead to MDA formation, we hypothesized that CYP2E1 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 μM 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 μM/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 HBECs 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 CYP2E1 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.",
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T1 - Protective Role of CYP2E1 Inhibitor diallyl disulfide (DADS) on Alcohol-induced malondialdehyde-deoxyguanosine (M1dG) adduct formation

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AU - Hottor, Tete K.

AU - Devasure, Jane M.

AU - Wyatt, Todd A

AU - Mccaskill, Michael L.

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N2 - 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 (CYP2E1). 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 CYP2E1 regulates MDA production, and our previous studies have shown that alcohol and cigarette smoke can lead to MDA formation, we hypothesized that CYP2E1 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 μM 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 μM/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 HBECs 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 CYP2E1 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.

AB - 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 (CYP2E1). 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 CYP2E1 regulates MDA production, and our previous studies have shown that alcohol and cigarette smoke can lead to MDA formation, we hypothesized that CYP2E1 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 μM 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 μM/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 HBECs 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 CYP2E1 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.

KW - CYP2E1

KW - DADS

KW - EtOH

KW - M1dG

KW - Malondialdehyde

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