Regioselective Metabolism of Taxoids by Human CYP3A4 and 2C8: Structure-Activity Relationship

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Paclitaxel and docetaxel are metabolized by liver microsomal monooxygenases into inactive metabolites further eliminated from the body via the bile route. In spite of their close chemical structure, the two drugs are oxidized by two different enzymes; CYP2C8 catalyzes the 6-hydroxylation on the taxane ring of paclitaxel, whereas CYP3A4 oxidizes docetaxel on the tert-butyl group of the lateral chain in C13. Since paclitaxel and docetaxel differ only by two substitutions, the role of individual modifications was investigated; the regioselectivity of hydroxylation was assessed by highpressure liquid chromatography/mass spectrometry, and enzymes implicated in individual reactions were identified using human liver microsomes and recombinant P450 expressed in Ad293 cells. The biotransformation of docetaxel, 10-deacetylpaclitaxel, and 10-deacetylbaccatin III was steadily increased (2-to 5-fold) by the addition of an acetyl group in position 10, suggesting that the presence of a hydrophobic group in position 10 stimulated hydroxylation by P450 proteins. The absence of the lateral chain at C13 in baccatin III severely impaired the metabolism supported by CYP3A4. The presence of a tert-butyl group in the lateral chain of docetaxel favored the hydroxylation on the tert-butyl by CYP3A4, whereas the presence of a phenyl group in the lateral chain facilitated the oxidation on the taxane ring by CYP2C8. Collectively, these data strongly suggested that the structure of the lateral chain and the nature of substituent in position 10 play an important role in determining the regioselective oxidation by P450 proteins and modulate the reaction rate by human liver microsomes.

Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes

“…Furthermore, it has been recently shown that microsomes from colorectal cancer samples have the ability to convert paclitaxel to a less cytotoxic metabolite, 3V-p-hydroxypaclitaxel (43); this metabolic reaction is known to be selectively catalyzed by CYP3A4 (44). Besides paclitaxel, CYP3A4 has been shown to be involved in the metabolic inactivation of several other anticancer agents such as docetaxel, Vinca alkaloids, and irinotecan (44 -46).…”

Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes

“…Although cDNA microarray analysis had suggested that a large number of genes correlated in expression levels with the cytotoxicities of the 8 drugs, the candidates included very few genes known as drug-sensitivity determinants (Table II) 21,[23][24][25][26] The results also suggested a novel relationship between gene expression levels and drug sensitivities, such as MGMT and TOPO2A for SN-38 and TUBB for TXL. 19,21,22,27,28 Including these 5 genes, we finally selected a total of 13 genes as the earliest candidates for prediction markers of response to the 8 drugs.…”

“…19,21,22,27,28 Including these 5 genes, we finally selected a total of 13 genes as the earliest candidates for prediction markers of response to the 8 drugs.…”

Drug‐Metabolizing Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition

“…Docetaxel metabolism requires CYP3A, with evidence for involvement of both CYP3A4 and CYP3A5 (Shou et al, 1998;Cresteil et al, 2002). There have been reports that docetaxel metabolism is inhibited by coadministration with erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin, and that it is induced by the classic CYP3A inducers, dexamethasone and rifampicin (Marre et al, 1996).…”

“…Tamoxifen and toremifene are oxidized by CYPs to pharmacologically active and inactive metabolites and also to reactive products with genotoxic potential (Boocock et al, Huang et al, 2000;Murray et al, 1994 Long andDolan, 2001;Reid et al, 1999Cresteil et al, 2002Shou et al, 1998Takara et al, 2002Relling et al, 1994Kawashiro et al, 1998 Flavopiridol Ifosfamide 2002; Crewe et al, 2002). Several CYPs seem to be involved in these pathways, with the oxidation of tamoxifen as the prototypic agent in this class being particularly well studied; biotransformation of toremifene has been less well investigated (Kim et al, 2003).…”