title: Enhanced oxidative stress by alcohol use in HIV+ patients: possible involvement of cytochrome P450 2E1 and antioxidant enzymes.
abstract: BACKGROUND
  Alcohol 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Compared 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108 USA.
authors.forename: Anusha
authors.initials: A
authors.lastname: Ande
authors.affiliation: College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163 USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Sinha
authors.affiliation: College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163 USA.
authors.forename: P S S
authors.initials: PS
authors.lastname: Rao
authors.affiliation: School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108 USA.
authors.forename: Carole P
authors.initials: CP
authors.lastname: McArthur
authors.affiliation: Regional Hospital, Box 818, Bamenda, North West Province Cameroon.
authors.forename: Leo
authors.initials: L
authors.lastname: Ayuk
authors.affiliation: Mezam Polyclinic HIV/AIDS Treatment Center, Bamenda, Cameroon.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Achu
authors.affiliation: Mezam Polyclinic HIV/AIDS Treatment Center, Bamenda, Cameroon.
authors.forename: Annette
authors.initials: A
authors.lastname: Njinda
authors.affiliation: School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108 USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163 USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
keywords: Alcohol; Antioxidant enzymes; Cytochrome P450; Cytokines; HIV; Oxidative stress