Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate.
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Chowdhury G, Murayama N, Okada Y, Uno Y, Shimizu M, Shibata N, Guengerich FP, Yamazaki H
Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate.
Chem Res Toxicol. 2010 Jun 21;23(6):1018-24. doi: 10.1021/tx900367p.
- PubMed ID
- 20443640 [ View in PubMed]
- Abstract
(R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reductase in bacterial membranes) also catalyzed (R)-thalidomide 5-hydroxylation. Purified human P450s 2C19, 3A4, and 3A5 mediated (R)-thalidomide 5-hydroxylation at similar rates in reconstituted systems. P450 2C19 showed a rather nonsaturable substrate-velocity curve; however, P450s 3A4 and 3A5 showed sigmoidal curves. P450 also oxidized 5-hydroxythalidomide to an epoxide or dihydroxy compound. Liquid chromatography-mass spectrometry analysis revealed the formation of a glutathione conjugate from (R)- and (S)-5-hydroxythalidomide, catalyzed by liver microsomal P450s 3A4 and 3A5 in the presence of glutathione (assigned as a conjugate of 5-hydroxythalidomide formed on the phenyl ring). These results indicate that human P450s 3A4 and 3A5 mediate thalidomide 5-hydroxylation and further oxidation leading to a glutathione conjugate, which may be of relevance in the pharmacological and toxicological actions of thalidomide.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Thalidomide Cytochrome P450 3A4 Protein Humans NoSubstrateInducerDetails Thalidomide Cytochrome P450 3A5 Protein Humans NoSubstrateInducerDetails