Enhanced oxidative stress by alcohol use in HIV+ patients: possible involvement of cytochrome P450 2E1 and antioxidant enzymes

Abstract

BackgroundAlcohol consumption is prevalent amongst HIV positive population. Importantly, chronic alcohol use is reported to exacerbate HIV pathogenesis. Although alcohol is known to increase oxidative stress, especially in the liver, there is no clinical evidence that alcohol increases oxidative stress in HIV positive patients. The mechanism by which alcohol increases oxidative stress in HIV positive patients is also unknown.MethodsTo examine the effects of alcohol use on oxidative stress we recruited HIV+ patients who reported mild-to-moderate alcohol use. Strict inclusion and exclusion criteria were applied to reduce the effect of other therapeutic drugs metabolized via the hepatic system as well as the effect of co-morbidities such as active tuberculosis on the interaction between alcohol and HIV infection, respectively. Blood samples were collected from HIV-negative alcohol-users and HIV positive alcohol-users followed by collection of plasma and isolation and fractionation of monocytes from peripheral blood. We then determined oxidative DNA damage, glutathione level, alcohol level, transcriptional level of cytochrome P450 2E1 (CYP2E1) and several antioxidant enzymes, and plasma level of cytokines.ResultsCompared to HIV-negative alcohol users, HIV-positive alcohol users demonstrated an increase in oxidative DNA damage in both plasma and CD14+ monocytes, as well as, a relative increase in oxidized/reduced glutathione (GSSG/GSH) in plasma samples. These results suggest an increase in oxidative stress in HIV-positive alcohol users compared with HIV-negative alcohol users. We also examined whether alcohol metabolism, perhaps by CYP2E1, and antioxidant enzymes are involved in alcohol-mediated increased oxidative stress in HIV-positive patients. The results showed a lower plasma alcohol level, which was associated with an increased level of CYP2E1 mRNA in monocytes, in HIV-positive alcohol users compared with HIV-negative alcohol users. Furthermore, the transcription of major antioxidants enzymes (catalase, SOD1, SOD2, GSTK1), and their transcription factor, Nrf2, were reduced in monocytes obtained from HIV positive alcohol users compared to the HIV-negative alcohol user group. However, no significant change in levels of five major cytokines/chemokines were observed between the two groups.ConclusionsThe data suggests that alcohol increases oxidative stress in HIV+ patients, perhaps through CYP2E1- and antioxidant enzymes-mediated pathways. The enhanced oxidative stress is accompanied by a failure of cellular antioxidant mechanisms to maintain redox homeostasis. Overall, the enhanced oxidative stress in monocytes may exacerbate HIV pathogenesis in HIV positive alcohol users.

Chronic Effects of Ethanol and/or Darunavir/Ritonavir on U937 Monocytic Cells: Regulation of Cytochrome P450 and Antioxidant Enzymes, Oxidative Stress, and Cytotoxicity

“…In agreement with the existing studies that suggest EtOH‐induced oxidative stress and tissue injury (Jimenez‐Lopez and Cederbaum, ), enhanced cell death was observed in chronic EtOH ± ART treated U937 cells. The current finding also correlated with our recent data from monocytes collected from HIV+ alcohol users in which significant induction of CYP2E1, in association with enhanced oxidative stress, was observed in comparison to EtOH users (Ande et al, b).…”

“…Chronic EtOH administration in non human primates has already been shown to enhance simian immunodeficiency virus replication and progression of disease (Bagby et al., ). Importantly, in a recently published article, we have demonstrated, for the first time, an alcohol‐induced up‐regulation of CYP expression and increased oxidative stress in monocytes collected from HIV‐infected individuals (Ande et al., 2015b). The data from this study suggest that alcohol‐induced oxidative stress in HIV‐infected alcohol users is mediated perhaps through an increased expression of CYP2E1 that is consistent with a decreased level of plasma alcohol in these individuals.…”

Gene expression patterns associated with neurological disease in HIV infection

“…In HIVE, multiple pathways indicative of impaired mitochondria and energy metabolism were differentially regulated. In NCI without HIVE, we observed increased expression of cytochrome P450 enzymes, which may indicate oxidative stress (55).…”

Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected Monocytes, and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding Studies

“…5). Ethanol induced HIV replication in monocytes cells appears to be via CYP2E1-mediated alcohol metabolism and resultant oxidative stress (7,11,23). Similar to 20 mM ethanol concentration, ethanol-induced increase in HIV replication was completely abolished when cells were treated with DRV or DRV + RTV at both 10 mM and 50 mM ethanol concentrations ( p < 0.05 compared to control or ethanol, student t test).…”