Vitamin C protective role for alcoholic liver disease in mice through regulating iron metabolism

Guo, Xiaoqiang; Li, Wenjie; Xin, Qiliang; Ding, Hui; Zhang, Caiyun; Chang, Yan-Zhong; Duan, Xingguang

doi:10.1177/0748233710387007

Cited by 25 publications

(12 citation statements)

References 31 publications

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“…Chronic accumulation of ROS leads to over consumption of glutathione and antioxidants, leading to cellular toxicity [52]. The use of antioxidant supplements, such as vitamin C and E, has been shown to be effective in attenuating the oxidative stress-mediated effects of alcoholic liver disease [53]. Our findings suggest the potential use of a CYP2E1 selective inhibitor [19] among alcohol and tobacco users to reduce alcohol-mediated oxidative stress and induction of CYP2A6 expression and activity, which can further increase oxidative stress through nicotine metabolism.…”

Section: Discussionmentioning

confidence: 99%

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Jin

Kumar

2012

PLoS ONE

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Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (∼150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol-induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV-infected individuals.

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Section: Discussionmentioning

confidence: 99%

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Jin

Kumar

2012

PLoS ONE

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“…Therefore, examination of the role of these CYP enzymes would further aid in development of novel pharmaceuticals using selective inhibitors of these CYP enzymes. It is possible that specific anti-oxidants, such as vitamin C, vitamin E, melatonin and taurine, which are very effective in alleviating oxidative stress mediated damage in alcoholic liver disease [85], could also reduce nicotine/tobacco-mediated HIV-1 pathogenesis.…”

Section: Expert Opinionmentioning

confidence: 99%

Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes

Ande

McArthur

Kumar

et al. 2013

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Tobacco smoking is highly prevalent among the HIV-1-infected population. In addition to diminished immune response, smoking has been shown to increase HIV-1 replication and decrease response to antiretroviral therapy, perhaps through drug–drug interaction. However, the mechanism by which tobacco/nicotine increases HIV-1 replication and mediates drug–drug interaction is poorly understood. Areas covered In this review, the authors discuss the effects of smoking on HIV-1 pathogenesis. Since they propose a role for the cytochrome P450 (CYP) pathway in smoking-mediated HIV-1 pathogenesis, the authors briefly converse the role of CYP enzymes in tobacco-mediated oxidative stress and toxicity. Finally, the authors focus on the role of CYP enzymes, especially CYP2A6, in tobacco/nicotine metabolism and oxidative stress in HIV-1 model systems monocytes/macrophages, lymphocytes, astrocytes and neurons, which may be responsible for HIV-1 pathogenesis. Expert opinion Recent findings suggest that CYP-mediated oxidative stress is a novel pathway that may be involved in smoking-mediated HIV-1 pathogenesis, including HIV-1 replication and drug–drug interaction. Thus, CYP and CYP-associated oxidative stress pathways may be potential targets to develop novel pharmaceuticals for HIV-1-infected smokers. Since HIV-1/TB co-infections are common, future study involving interactions between antiretroviral and antituberculosis drugs that involve CYP pathways would also help treat HIV-1/TB co-infected smokers effectively.

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“…Given the strong bidirectional, and possibly therapeutic, link between vitamin C treatment and alcohol consumption, one would have expected a push for trials looking at vitamin C supplementation in chronic alcoholics. However, to date, vitamin C supplementation has only been proven to ameliorate ethanol-induced hepatotoxicity in mice, 29 not humans, while RCTs, as stated above, 6–8 have not looked into the at-risk subpopulation of chronic alcoholic use. This is manifested in the present-day guidelines on alcohol withdrawal which provide scant instruction on vitamin C supplementation regimen or route ( table 2 ).…”

Section: Introductionmentioning

confidence: 99%