ToxSci Advance Access originally published online on March 15, 2008
Toxicological Sciences 2008 103(2):335-345; doi:10.1093/toxsci/kfn056
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In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone, and Buspirone
* Drug Safety Research and Development, Pfizer, Inc., Sandwich, UK CT139NJ
Drug Safety Research and Development, Pfizer, Inc., San Diego, California 92121
MitoSciences, Inc., Eugene, Oregon 97403
Systems Biology, Pfizer Research Technology Center, Pfizer, Inc., Cambridge, Massachusetts 02139
¶ Exploratory Safety Differentiation, Pfizer, Inc., Eastern Point, Groton, Connecticut 06340
1 To whom correspondence should be addressed. Fax: (860) 441-9637. E-mail: yvonne.will{at}pfizer.com.
Received January 24, 2008; accepted March 5, 2008
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Abstract |
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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 Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity.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.
Key Words: nefazodone; trazodone; buspirone; hepatotoxicity; mitochondria; drug toxicity.