Acrolein enhances anti‐HIV‐ HAART medication‐ induced hepatotoxicity

Highly active antiretroviral therapy (HAART) has significantly increased the life expectancy of patients with HIV infection. However, HAART‐ associated hepatotoxicity is becoming a major clinical problem and can be potentially compounded by exposure to diet/environment ‐ derived reactive aldehydes, particularly acrolein. The present study investigates the combined effects of acrolein along with HAART drug, azidothymidine (AZT) in a human hepatocyte cell line (HepG2). Our results showed that exposure to either acrolein or AZT had minimal to no effect on hepatocyte survival. However acrolein in combination with AZT led to a significant increase in hepatocyte apoptotic death. The increase in apoptosis was accompanied by transcriptionally permissive H3 histone acetylation at FasL‐promoter and consequent FasL gene expression. Interestingly, concomitant with the induction of FasL and apoptotic death there was a significant attenuation of autophagy as indicated by a decrease in Beclin‐1 and an increase in LC3II/LC3I ratio. These data strongly suggest that the mechanisms underpinning acrolein‐AZT mediated hepatotoxicity involves the suppression of autophagy and induction of FasL mediated apoptosis. Overall, the data suggest that presence of diet/environment derived reactive aldehydes can play a pathogenic role in HIV patients by enhancing HAART‐hepatotoxicity. This work was supported by NIH grants.