ToxSci Advance Access published online on March 15, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn056
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In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone and Buspirone
1 Drug Safety Research and Development, Pfizer, Inc., Ramsgate Road, Sandwich, England CT139NJ 2 Drug Safety Research and Development, Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121 3 MitoSciences, Inc., 1850 Millrace Drive, Eugene, OR 97403 4 Systems Biology, Pfizer Research Technology Center, Pfizer, Inc., 620 Memorial Drive, Cambridge, MA 02139 5 Exploratory Safety Differentiation, Pfizer, Inc., Eastern Point, Groton CT 06340
* To whom correspondence should be addressed. Fax: (860) 441-9637, Phone : (860) -686-2832, E-mail: yvonne.will{at}pfizer.com.
Received January 24, 2008; revision received March 5, 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 Nefazodone was withdrawn from the US market in 2004 due to hepatotoxicity.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, while 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 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 CYP3A4, after 24 hr 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 co-treated with other drugs with mitochondrial liabilities.
Key Words: nefazodone; trazodone; buspirone; hepatotoxicity; mitochondria; drug toxicity.