ABCG2 Pharmacogenetics

Abstract

Purpose: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan.Experimental Design: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies.Results: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng ؋ hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide.Conclusions: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.

ATP-binding cassette, subfamily G (ABCG family)

“…Such a discrepancy cannot be explained from a pharmacokinetic viewpoint, and the effect of such a polymorphism on the plasma concentration should be theoretically clearer after oral administration. In another report, the area under the curve of the plasma concentration of rosuvastatin following a single oral administration was greater in the hetero-and homozygotes [89], but heterozygotes did not show any difference in the pharmacokinetic profile of irinotecan and its active metabolite SN-38 [15].…”

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…This is particularly pertinent, given the fact that the Japanese and Han Chinese populations have markedly higher ABCG2 421C4A allele frequencies (30.7 and 28.9%, respectively) than do Caucasian (11.7%) and African-American populations (2.3%). [47][48][49] Our group is currently pursuing a prospective clinical study to validate this prediction formula.…”

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

“…ABCB1 appears to be the main paclitaxel transporter 23,24 and variants in ABCB1 have been demonstrated to alter P-glycoprotein expression. 25,26 A nonsynonymous variant in ABCG2 (421C4A; Q141K) has been associated with drug resistance in vitro and in vivo, [27][28][29] and with survival in prostate cancer patients receiving docetaxel chemotherapy (P ¼ 0.05), 30 consequently, despite the lack of evidence associating taxane transport with ABCG2 the 421C4A variant was included in this study.…”