In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone, and Buspirone

Abstract

Mitochondrial toxicity is increasingly implicated in a host of drug-induced organ toxicities, including hepatotoxicity. Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity. Accordingly, we evaluated nefazodone, another triazolopyridine trazodone, plus the azaspirodecanedione buspirone, for cytotoxicity and effects on mitochondrial function. In accord with its clinical disposition, nefazodone was the most toxic compound of the three, trazodone had relatively modest effects, whereas buspirone showed the least toxicity. Nefazodone profoundly inhibited mitochondrial respiration in isolated rat liver mitochondria and in intact HepG2 cells where this was accompanied by simultaneous acceleration of glycolysis. Using immunocaptured oxidative phosphorylation (OXPHOS) complexes, we identified Complex 1, and to a lesser amount Complex IV, as the targets of nefazodone toxicity. No inhibition was found for trazodone, and buspirone showed 3.4-fold less inhibition of OXPHOS Complex 1 than nefazodone. In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. Our results suggest that the mitochondrial impairment imposed by nefazodone is profound and likely contributes to its hepatotoxicity, especially in patients cotreated with other drugs with mitochondrial liabilities.

Fluvoxamine alters the activity of energy metabolism enzymes in the brain

“…31 Recent studies showed that citalopram and escitalopram decreased the activity of respiratory chain complexes. 32 Dykens et al 33 showed that antidepressants induce mitochondrial dysfunction and cytotoxicity. In this context, a recent study showed that tricyclic antidepressants can modulate mitochondrial functions indirectly through a decrease in nitric oxide production.…”

Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

“…The same work showed that NEF treatment resulted in inhibition of both bile acid transport, via the bile salt export pump (BSEP) present in membrane vesicles, and the canalicular transport in cultured human hepatocytes (Kostrubsky et al, 2006). NEF was also shown to directly impair hepatic mitochondrial function through inhibition of OXPHOS complexes, particularly complex I (Dykens et al, 2008;Nadanaciva et al, 2007). Although mitochondrial dysfunction seems to be a major player behind NEF hepatotoxicity, there are only a few reports describing the possible mechanisms involved (Dykens et al, 2008;Kim et al, 2012;Swiss et al, 2013;Xu et al, 2008).…”

“…NEF was also shown to directly impair hepatic mitochondrial function through inhibition of OXPHOS complexes, particularly complex I (Dykens et al, 2008;Nadanaciva et al, 2007). Although mitochondrial dysfunction seems to be a major player behind NEF hepatotoxicity, there are only a few reports describing the possible mechanisms involved (Dykens et al, 2008;Kim et al, 2012;Swiss et al, 2013;Xu et al, 2008). Dykens et al, reported that NEF treatment resulted in a decreased mitochondrial transmembrane electric potential (DJ m ), a marked reduction in the intracellular levels of reduced glutathione, and a rise in the levels of reactive oxygen species (ROS) in primary cultures of human hepatocytes (Dykens et al, 2008).…”

“…Although mitochondrial dysfunction seems to be a major player behind NEF hepatotoxicity, there are only a few reports describing the possible mechanisms involved (Dykens et al, 2008;Kim et al, 2012;Swiss et al, 2013;Xu et al, 2008). Dykens et al, reported that NEF treatment resulted in a decreased mitochondrial transmembrane electric potential (DJ m ), a marked reduction in the intracellular levels of reduced glutathione, and a rise in the levels of reactive oxygen species (ROS) in primary cultures of human hepatocytes (Dykens et al, 2008). A dramatic reduction in oxygen consumption by isolated rat liver mitochondria incubated with NEF was also observed in the same study, followed by an increase in the extracellular acidification rate (ECAR) (Dykens et al, 2008).…”

“…Dykens et al, reported that NEF treatment resulted in a decreased mitochondrial transmembrane electric potential (DJ m ), a marked reduction in the intracellular levels of reduced glutathione, and a rise in the levels of reactive oxygen species (ROS) in primary cultures of human hepatocytes (Dykens et al, 2008). A dramatic reduction in oxygen consumption by isolated rat liver mitochondria incubated with NEF was also observed in the same study, followed by an increase in the extracellular acidification rate (ECAR) (Dykens et al, 2008). Further evidence regarding mitochondrial involvement in the reported NEF toxicity came from observation of depleted ATP levels in HepG2 cells upon NEF treatment (Dykens et al, 2008).…”