Ana Blas-García1, Alberto Martí-Rodrigo2, Víctor M Víctor3, Miriam Polo4, Fernando Alegre4, Haryes A Funes2, Nadezda Apostolova5, Juan V Esplugues6. 1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain CIBERehd, Valencia, Spain ana.blas@uv.es. 2. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. 3. FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain CIBERehd, Valencia, Spain. 4. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain. 5. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain CIBERehd, Valencia, Spain Facultad de Ciencias de la Salud, Universidad Jaime I, Castellón de la Plana, Spain. 6. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain CIBERehd, Valencia, Spain.
Abstract
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.
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.
Authors: Joseph W George; Jane E Mattingly; Nashanthea J Roland; Cassandra M Small; Benjamin G Lamberty; Howard S Fox; Kelly L Stauch Journal: Front Immunol Date: 2021-05-20 Impact factor: 7.561