Impairing Cytochrome P450-mediated metabolism aggravates the hepatoxicity of serotonin and norepinephrine reuptake inhibitor duloxetine

Abstract

<b>Abstract ID 24646</b> <b>Poster Board 20</b> Duloxetine (DLX), a dual serotonin and norepinephrine reuptake inhibitor for the treatment of major depressive disorder, is mainly metabolized by CYP1A2 and CYP2D6 in human. Despite DLX has a good tolerance for most patients, the cases with serious liver injury have been reported. Here, we investigated the roles of P450-mediated metabolism in the DLX hepatotoxicity <i>in&nbsp;vitro</i> and <i>in&nbsp;vivo</i>. We found that DLX is less toxic to CYP1A2- or CYP2D6-overexpressed HepG2 cells compared to their counterpart HepG2 cells transduced with empty vector, indicating that P450-mediated metabolism attenuates DLX cytotoxicity to HepG2. The CYP1A2 (α-naphthoflavone and fluvoxamine) or CYP2D6 inhibitors (paroxetine, fluoxetine, and quinidine) significantly enhanced the toxicity of DLX to human primary hepatocytes. In Cyp1a2-knockout (Cyp1a2-KO) and <i>counterpart</i> wild-type (WT) mice, 50 mg/kg or 100 mg/kg (p.o.) of DLX for consecutive 5 days did not significantly increase the plasma ALT and AST levels compared with the vehicle group in both WT and Cyp1a2-KO mice, suggesting that Cyp1a2 is not a fundamental contributor to DLX detoxification at least in mice. However, DLX and a mouse Cyp2d inhibitor propranolol in both WT and Cyp1a2-KO mice lead to severe liver injury. The ALT levels increased for 2.9- and 8.7-fold in 50 mg/kg and 100 mg/kg groups, respectively in WT mice co-treated with propranolol. Similar increased folds of ALT were also observed in Cyp1a2-KO mice. H&amp;E staining of mouse livers also confirmed the liver toxicity, presented as cell necrosis, in 100 mg/kg group in both WT and Cyp1a2-KO mice with the co-treatment of Cyp2d inhibitor. In summary, our findings suggests that impairing P450-mediated metabolism exacerbates DLX hepatoxicity <i>in&nbsp;vitro</i> and <i>in&nbsp;vivo</i>. Further studies are warranted to verify the roles of CYP1A2 and CYP2D6 in DLX liver toxicity using liver humanized mice and their inhibitors. This work was supported by the NIDDK (R01DK121970) and NICHD (R61/33HD099995) to Dr. Feng Li. Feng Li was also partially supported by the NICHD (P01 HD087157, R01HD110038) to Dr. Martin M. Matzuk.