Potential role of UGT1A4 promoter SNPs in anastrozole pharmacogenomics.
Anastrozole belongs to the nonsteroidal triazole-derivative group of aromatase inhibitors. Recently, clinical trials demonstrated improved antitumoral efficacy and a favorable toxicity with third-generation aromatase inhibitors, compared with tamoxifen. Anastrozole is predominantly metabolized by phase I oxidation with the potential for further phase II glucuronidation. It also, however, is subject to direct N-glucuronidation by UDP-glucuronosyltransferase 1A4 (UGT1A4). Anastrozole pharmacokinetics vary widely among patients, but pharmacogenomic studies of patients treated with anastrozole are sparse. In this study, we examined individual variability in the glucuronidation of anastrozole and its association with UGT1A4 promoter and coding region polymorphisms. In vitro assays using liver microsomal preparations from individual subjects (n = 96) demonstrated 235-fold variability in anastrozole glucuronidation. Anastrozole glucuronidation was correlated (r = 0.99; P < 0.0001) with lamotrigine glucuronidation (a diagnostic substrate for UGT1A4) and with UGT1A4 mRNA expression levels in human liver microsomes (r = 0.99; P < 0.0001). Recombinant UGT1A4 catalyzed anastrozole glucuronidation, which was inhibited by hecogenin (IC50 = 15 µM), a UGT1A4 specific inhibitor. The promoter region of UGT1A4 is polymorphic, and compared with those homozygous for the common allele, lower enzymatic activity was observed in microsomes from individuals heterozygous for -163G<A, -219T<G, and -217C<T (P = 0.009, P = 0.014, and P = 0.009, respectively). These results indicate that variability in glucuronidation could contribute to response to anastrozole in the treatment of breast cancer.
Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Vineetha Koroth
VK
Edavana
Ishwori B
IB
Dhakal
Suzanne
S
Williams
Rosalind
R
Penney
Gunnar
G
Boysen
Aiwei
A
Yao-Borengasser
Susan
S
Kadlubar
D000077384:Anastrozole; D000927:Anticonvulsants / Q000493:pharmacokinetics; D047072:Aromatase Inhibitors / Q000493:pharmacokinetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic / Q000235:genetics*; D000077213:Lamotrigine; D008862:Microsomes, Liver / Q000378:metabolism; D009570:Nitriles / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012502:Sapogenins / Q000494:pharmacology; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D047072:Aromatase Inhibitors; D009570:Nitriles; D012502:Sapogenins; D014227:Triazines; D014230:Triazoles; C019787:bilirubin glucuronoside glucuronosyltransferase; D000077384:Anastrozole; C007908:hecogenin; D014453:Glucuronosyltransferase; D000077213:Lamotrigine