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RESEARCH PRODUCT

The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction

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Background NRTIs are essential components of HIV therapy with well-documented, long-term mitochondrial toxicity in hepatic cells, but whose acute effects on mitochondria are unclear. As acetaminophen-induced hepatotoxicity also involves mitochondrial interference, we hypothesized that it would be exacerbated in the context of ART. Methods We evaluated the acute effects of clinically relevant concentrations of the most widely used NRTIs, alone or combined with acetaminophen, on mitochondrial function and cellular viability. Results The purine analogues abacavir and didanosine produced an immediate and concentration-dependent inhibition of oxygen consumption and complex I and III activity. This inhibition was accompanied by an undermining of mitochondrial function, with increased production of reactive oxygen species and reduction of mitochondrial membrane potential and intracellular ATP levels. However, this interference did not compromise cell survival. Co-administration with concentrations of acetaminophen below those considered hepatotoxic exacerbated the deleterious effects of both compounds on mitochondrial function and compromised cellular viability, showing a clear correlation with diminished glutathione levels. Conclusions The simultaneous presence of purine analogues and low concentrations of acetaminophen significantly potentiates mitochondrial dysfunction, increasing the risk of liver injury. This new mechanism is relevant given the liver's susceptibility to mitochondrial dysfunction-related toxicity and the tendency of the HIV infection to increase oxidative stress. This work was supported by the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad [grants PI11/00327, PI13/1025, PI14/00312 and CIBER CB06/04/0071], and postgraduate research grant FI12/00198 awarded to F.A.; the Conselleria d'Educació, Formació i Ocupació, Generalitat Valenciana [grants PROMETEO/2010/060, PROMETEOII/2014/035, ACOMP/2013/236 and GVA/2014/118] and postgraduate research grant ACIF/2013/136 awarded to M.P.; the Universitat Jaume I [grant P1.1B-2014/15]; the Ministerio of Economía y Competitividad [Juan de la Cierva contract JCI-2012–15124 to A.B.-G.]; the Ministerio de Sanidad and Generalitat Valenciana [contract CES10/030 to V.M.V]; and the Ministerio de Educación, Cultura y deporte [postgraduate research grant FPU13/00151 to A.M.-R.].