The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2α were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPARα as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid β-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, et al. (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338: 853–860.
Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, et al. (2006) Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 43: 27–34.
Carr A, Miller J, Law M, Cooper DA (2000) A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 14: F25–32.
Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, et al. (2002) Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 16: 2183–2193.
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD (2000) Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 283: 74–80.
Chariot P, Drogou I, de Lacroix-Szmania I, Eliezer-Vanerot MC, Chazaud B, et al. (1999) Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 30: 156–160.
de la Asuncion JG, del Olmo ML, Sastre J, Millan A, Pellin A, et al. (1998) AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. J Clin Invest 102: 4–9.
Szabados E, Fischer GM, Toth K, Csete B, Nemeti B, et al. (1999) Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. Free Radic Biol Med 26: 309–317.
Manda KR, Banerjee A, Banks WA, Ercal N (2011) Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells. Free Radic Biol Med 50: 801–810.
Abdelmegeed MA, Banerjee A, Yoo SH, Jang S, Gonzalez FJ, et al. (2012) Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol 57: 860–866.
Abdelmegeed MA, Jang S, Banerjee A, Hardwick JP, Song BJ (2013) Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury. Free Radic Biol Med Epub ahead of print.
Kimzey AL, Weitz KK, Guengerich FP, Zangar RC (2003) Hydroperoxy-10,12-octadecadienoic acid stimulates cytochrome P450 3A protein aggregation by a mechanism that is inhibited by substrate. Biochemistry 42: 12691–12699.
Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD (2004) Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 18: 2277–2284.
Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, et al. (2000) CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. Journal of Clinical Investigation 105: 1067–1075.
Wu J, Zhao MY, Zheng H, Zhang H, Jiang Y (2010) Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression. Acta Pharmacol Sin 31: 1367–1375.
Guimaraes EL, Empsen C, Geerts A, van Grunsven LA (2010) Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. J Hepatol 52: 389–397.
Gao RY, Mukhopadhyay P, Mohanraj R, Wang H, Horvath B, et al. (2011) Resveratrol attenuates azidothymidine-induced cardiotoxicity by decreasing mitochondrial reactive oxygen species generation in human cardiomyocytes. Mol Med Rep 4: 151–155.
Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, et al. (1996) Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98: 1575–1584.
Garcia-Villafranca J, Guillen A, Castro J (2008) Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver. Biochimie 90: 460–466.