PT  - JOURNAL ARTICLE
AU  - Ganesh M. Mugundu
AU  - Larry Sallans
AU  - Yingying Guo
AU  - Elizabeth A. Shaughnessy
AU  - Pankaj B. Desai
TI  - Assessment of the Impact of CYP3A Polymorphisms on the Formation of α-Hydroxytamoxifen and <em>N</em>-Desmethyltamoxifen in Human Liver Microsomes
AID  - 10.1124/dmd.111.039388
DP  - 2012 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 389--396
VI  - 40
IP  - 2
4099  - http://dmd.aspetjournals.org/content/40/2/389.short
4100  - http://dmd.aspetjournals.org/content/40/2/389.full
SO  - Drug Metab Dispos2012 Feb 01; 40
AB  - Tamoxifen, an antiestrogen used in the prevention and treatment of breast cancer, is extensively metabolized by cytochrome P450 enzymes. Its biotransformation to α-hydroxytamoxifen (α-OHT), which may be genotoxic, and to N-desmethyltamoxifen (N-DMT), which is partially hydroxylated to 4-hydroxy-N-DMT (endoxifen), a potent antiestrogen, is mediated by CYP3A enzymes. However, the potential contribution of CYP3A5 and the impact of its low-expression variants on the formation of these metabolites are not clear. Therefore, we assessed the contributions of CYP3A4 and CYP3A5 and examined the impact of CYP3A5 genotypes on the formation of α-OHT and N-DMT, by using recombinant CYP3A4 and CYP3A5 and human liver microsomes (HLM) genotyped for CYP3A5 variants. We observed that the catalytic efficiency [intrinsic clearance (CLint)] for α-OHT formation with recombinant CYP3A4 was 5-fold higher than that with recombinant CYP3A5 (0.81 versus 0.16 nl · min−1 · pmol cytochrome P450−1). There was no significant difference in CLint values between the three CYP3A5-genotyped HLM (*1/*1, *1/*3, and *3/*3). For N-DMT formation, the CLint with recombinant CYP3A4 was only 1.7-fold higher, relative to that with recombinant CYP3A5. In addition, the CLint for N-DMT formation by HLM with CYP3A5*3/*3 alleles was approximately 3-fold lower than that for HLM expressing CYP3A5*1/*1. Regression analyses of tamoxifen metabolism with respect to testosterone 6β-hydroxylation facilitated assessment of CYP3A5 contributions to the formation of the two metabolites. The CYP3A5 contributions to α-OHT formation were negligible, whereas the contributions to N-DMT formation ranged from 51 to 61%. Our findings suggest that polymorphic CYP3A5 expression may affect the formation of N-DMT but not that of α-OHT.