ABCB1 3435TT Research Articles

The role of ABC-transporter gene polymorphisms in chemotherapy induced immunosuppression, a retrospective study in childhood acute lymphoblastic leukaemia

We examined the association of functional ABCB1 ( MDR1) and ABCG2 (BCRP) polymorphisms with acute side effects of chemotherapy. Analyses were performed on clinical data from 138 patients treated with the ALL-BFM-95 protocol implying several substrates of these transporters. ABCB1 3435T>C, 2677G>T/A 1236C>T and ABCG2 421C>A genotypes were determined. A higher proportion of ABCB1 3435TT patients suffered excessive infectious complications than those harbouring at least one C allele (OR = 2.5, p = 0.03) during the whole half-year-long intensive phase of chemotherapy. Weaker associations were calculated when ABCB1 1236T-2677T-3435T haplotype homozygotes were tested against the remaining part of the population (OR = 2.3, p = 0.09). During the reinduction phase of therapy, the occurrence of severe leukocytopenia was similar among ABCB1 genotype groups. The frequency of any toxicities were not shown to differ according to the ABCG2 421C>A genotype. Our data suggest that the ABCB1 3435T>C genotype is associated with the infectious complications of the applied chemotherapy regimen.

ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment

The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Competing Influences of Genetic and Leukaemia-Specific Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the NCRN AML14 and 15 Trials.

Background. P-glycoprotein (pgp), expressed on acute myeloid leukaemia (AML) blasts, is associated with failure to respond to chemotherapy in AML. This study aimed to determine whether expression and function of pgp may be linked to polymorphisms of the encoding gene (MDR1, also known as ABCB1) and whether leukaemia-specific changes in cell biology may override genetic factors in predicting pgp expression. G1199A, G2677T and C3435T polymorphisms in MDR1 (RFLP analysis) as well as pgp protein expression (using MRK-16) and function (modulation of R123 accumulation by PSC 833) were studied in leukaemic blast samples from 817 patients with AML entered into the NCRN AML14 and AML15 clinical trials.Age, low white blood cell count (WBC), high bcl2, secondary AML and MDS and adverse cytogenetics all correlated with high pgp expression. However, ABCB1 3435TT homozygosity had a negative impact on pgp. Overall, pgp expression was high in 41% of the cohort, but in elderly patients high pgp expression was found in 54% with the 3435C allele versus 32% in the 3435TT group (P=0.009). This is similar to the frequency of pgp in younger patients (34%) and indicates that the 3435TT polymorphism affects pgp expression in elderly patients by preventing the upregulation of pgp protein normally seen in this group. No association was found between genetic factors and pgp function. In a subset of 341 patients, pgp protein levels were analysed on a quantitative scale in relation to C3435T and G2677T gene polymorphisms. The lowest protein expression occurred in the variant TT group for both polymorphisms. Differences were even more marked in the elderly subset (using Mann-Whitney test, P = 0.003 and 0.002 respectively). Linkage disequilibrium occurs between positions 2677 and 3435, and there was a highly significant association between the haplotype and pgp protein expression (P=0.001). ABCB1 mRNA was also measured in 81 patients and was found to be high in patients with the G1199A allele (median expression 0.36 ABCB1/b2M ratio v 0.06 in the GG group, P=0.04), suggesting that the 1199A polymorphism affects ABCB1. However no further correlations were found between the 1199A polymorphism and pgp protein or function. The association between pgp and a low white WBC, (P<0.001) was further examined by cell cycle analysis in 40 patients confirming that pgp is associated with a low proportion of cycling cells - median % cycling cells: pgp negative/low 4.0%, pgp intermediate/high 1.0% (P=0.02).Conclusions. We conclude that there is an extended MDR phenotype of indolent, pgp positive, bcl2-high cells in AML, particularly in the elderly, and that pgp is affected by an interaction between genetic factors and acquired, leukaemia-specific factors.

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C-->T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C-->T and 2677G-->T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (chi2 = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor's ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.