jm9b01990_si_002.pdf (3.02 MB)
Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death
journal contributionposted on 2020-02-27, 19:42 authored by Carley J. S. Heck, Herana Kamal Seneviratne, Namandjé N. Bumpus
Cytochrome P450-dependent metabolism of the anti-HIV drug nevirapine (NVP) to 12-hydroxy-NVP (12-OHNVP) has been implicated in NVP toxicities. We investigated the impact of twelfth-position trideuteration (12-D3NVP) on the hepatic metabolism of and response to NVP. Formation of 12-OHNVP decreased in human (10.6-fold) and mouse (4.6-fold) hepatocytes incubated with 10 μM 12-D3NVP vs NVP. An observed kinetic isotope effect of 10.1 was measured in human liver microsomes. During mouse hepatocyte treatment (400 μM) with NVP or 12-D3NVP, cell death was reduced 30% with 12-D3NVP vs NVP, while glucuronidated and glutathione-conjugated metabolites increased with 12-D3NVP vs NVP. Using mass spectrometry proteomics, changes in hepatocyte protein expression, including an increase in stress marker insulin-like growth factor-binding protein 1 (IGFBP-1), were observed with 12-D3NVP vs NVP. These results demonstrate that while deuteration can reduce P450 metabolite formation, impacts on phase II metabolism and hepatocyte protein expression should be considered when employing deuteration to reduce P450 metabolite-related hepatotoxicity.
Nevirapine-Induced Hepatocyte Death...P 450 metabolite-related hepatotoxicity12- Hydroxy-Nevirapine Formationphase II metabolism10 μ M 12- D 3 NVP vs NVPhepatic metabolismstress marker insulin-like growth f...NVP toxicities12- D 3 NVP vs NVPTwelfth-Position Deuterationmass spectrometry proteomicsglutathione-conjugated metabolites12- OHNVPP 450 metabolite formationIGFBP12- D 3 NVPliver microsomeshepatocyte protein expressionanti-HIV drug nevirapineisotope effectcell death