Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab


Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article


The nonsteroidal AI letrozole is metabolized to the pharmacologically inactive 4,4'-(hydroxymethylene)dibenzonitrile (carbinol), which is further glucuronidated to bis(4-cyanophenyl)methyl hexopyranosiduronic acid (carbinol-gluc).[115–117] Carbinol-gluc is the major metabolite of letrozole and approximately 65% of the oral letrozole dose is excreted as carbinol-gluc in the urine.[118] The conversion of letrozole to carbinol is catalyzed by CYP2A6 and CYP3A4.[116] The gene CYP2A6, located on chromosome 19q13.2,[119] is mainly expressed in human liver and contributes less than 5% to the total liver P450 pool.[25] CYP2A6 expression and function appear to be sex-dependent with higher levels in females.[120,121] Moreover, interindividual hepatic expression and function are highly variable.[122] In addition to transcriptional regulation of CYP2A6 by pregnane X receptor and constitutive androstane receptor activators, like rifampicin and phenobarbital[123] and the anti-inflammatory drug dexamethasone,[124] at least 38 CYP2A6 alleles have been identified so far,[205] in part with functional consequences.[122,125,126] For instance, the null alleles CYP2A6*2 and CYP2A6*4 (gene deletion) predispose to a PM phenotype. Of note, the CYP2A6*4 allele frequency differs widely between Europeans (1.2%) and Asians (10–20%).[127] Other impaired function alleles include *9B, *12B, *7, *10, *17 and *35. Due to the relevance of CYP2A6 in nicotine metabolism, several pharmacogenetic investigations were focused on smoking behavior, nicotine withdrawal symptoms and lung cancer risk.[128] With regard to letrozole, CYP2A6 genotype-predicted phenotypes showed a correlation to plasma levels of 261 postmenopausal breast cancer patients.[129] A Japanese clinical study investigated the influence of CYP2A6 polymorphisms as well as nongenetic factors on the population pharmacokinetics of letrozole in 25 healthy postmenopausal women.[130] The apparent systemic clearance (CL/F) was significantly altered by CYP2A6 genotype in that carriers of one or two variant alleles had reduced clearance of 84.3 and 44.8%, respectively. With respect to CYP3A5 genotypes, no association with letrozole plasma levels has been reported.[129]