Quinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapine: activation pathway to amino acid adducts

Abstract

Quinoid electrophiles from the nevirapine metabolites, 2-OH- and 3-OH-nevirapine, react with nitrogen-based bionucleophiles yielding covalent adducts.

Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death

“… 50 The formation of quinone and quinone methide reactive intermediates from 2-, 3-, and 12-OHNVP has been proposed, 23 , 24 , 51 , 52 with the formation of quinone derivatives from 2- and 3-OHNVP being previously captured and structurally characterized. 51 Quinone and quinone methide metabolites have been implicated in the mitochondrial toxicity of other drugs, such as tamoxifen, 53 and are thought not only to be bioreactive 24 , 51 but also to contribute to the toxic formation of mitochondrial superoxide anions. 54 The formation of protein-NVP adducts in the mitochondria or of damaging reactive oxygen species resulting from the formation of these quinone metabolites could explain our observed changes in mitochondrial protein expression.…”

“…FASTKD5 silencing results in assembly defects of complex IV of the electron transport chain . The formation of quinone and quinone methide reactive intermediates from 2-, 3-, and 12-OHNVP has been proposed, ,,, with the formation of quinone derivatives from 2- and 3-OHNVP being previously captured and structurally characterized . Quinone and quinone methide metabolites have been implicated in the mitochondrial toxicity of other drugs, such as tamoxifen, and are thought not only to be bioreactive , but also to contribute to the toxic formation of mitochondrial superoxide anions .…”