In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone.
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 Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity.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.
Dykens
James A
JA
Drug Safety Research and Development, Pfizer, Inc., Sandwich CT139NJ, UK.
Jamieson
Joseph D
JD
Marroquin
Lisa D
LD
Nadanaciva
Sashi
S
Xu
Jinghai J
JJ
Dunn
Margaret C
MC
Smith
Arthur R
AR
Will
Yvonne
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D002065:Buspirone / Q000633:toxicity*; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D014196:Trazodone / Q000633:toxicity*; D014230:Triazoles / Q000633:toxicity*
D014151:Anti-Anxiety Agents; D018687:Antidepressive Agents, Second-Generation; D010879:Piperazines; D014230:Triazoles; C051752:nefazodone; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D002065:Buspirone; D014196:Trazodone