ABCB1 p.Gly141Lys
| Predicted by SNAP2: | A: N (78%), C: D (66%), D: D (75%), E: D (59%), F: D (80%), H: D (66%), I: D (75%), K: D (85%), L: D (75%), M: D (75%), N: D (71%), P: D (71%), Q: D (75%), R: D (85%), S: N (72%), T: N (66%), V: N (61%), W: D (85%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] [Genetic marker of statin-induced rhabdomyolysis]. Yakugaku Zasshi. 2011 Feb;131(2):247-53. Chiba K, Morimoto K
[Genetic marker of statin-induced rhabdomyolysis].
Yakugaku Zasshi. 2011 Feb;131(2):247-53., [PMID:21297370]
Abstract [show]
This review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis.
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13 SLCO1B1 以外のトランスポーターの遺伝子 多型とスタチンの体内動態 最近,SLCO1B1 以外のトランスポーターの遺伝 子多型がスタチンの体内動態に影響を与えることが 次第に明らかとなっている．現時点ではまだ筋肉障 害との関係を明確にした報告はないが,ここではス タチンの血漿中濃度の比較的大きな変動要因となる ABCG2 と ABCB1 について述べることにする． ABCG2 は BCRP としても知られる ABC トラン スポーターである．小腸,肝臓,腎臓,脳,胎盤な ど広範な臓器に発現し,薬物などの脂溶性物質を排 出する役割を果たしている．ABCG2 には多くの SNPs が知られているが,比較的頻度が高く機能へ の影響も大きい 421C＞A(Gly141Lys)がスタチン との関係で最もよく検討されている．血漿中濃度へ の影響が最も大きいスタチンは,ロスバスタチン, アトルバスタチン,フルバスタチンであり,A-ア レルをホモ接合体として持つ個体は C-アレルのホ モ接合体と比較して,経口投与後の AUC がそれぞ れ 144%, 72%, 72%高くなる．24,25) シンバスタチン の AUC も A-アレルのホモ接合体で 111%高値を示 すが,アシッド型シンバスタチンの AUC には C- アレルと比較して有意な差は認められない．24,25) 一 方,プラバスタチン,ピタバスタチンの AUC は 421C＞A によって大きな影響を受けない．26,27) ABCB1 は P-糖タンパクとして知られている ABC トランスポーターである．小腸,肝臓,腎臓,脳な どに発現して,薬物を含む脂溶性物質の排出に係わ っている．このトランスポーターの遺伝子のハプロ タイプである 1236C-2677G-3435C をホモ接合体と して持つ個体ではアトルバスタチンとアシッド型シ ンバスタチンの AUC が 1236T-2677T-3435T をホモ 接合体として持つ個体より 5560%高いことが報告 されている．28) このハプロタイプはフルバスタチ ン,プラバスタチン,ロバスタチン,ロスバスタチ ンの体内動態には有意な影響を与えない．29) 5.
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ABCB1 p.Gly141Lys 21297370:13:2053
status: NEW[hide] The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2... Cancer Chemother Pharmacol. 2011 Jun;67(6):1471-8. Epub 2011 Apr 6. Chew SC, Singh O, Chen X, Ramasamy RD, Kulkarni T, Lee EJ, Tan EH, Lim WT, Chowbay B
The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients.
Cancer Chemother Pharmacol. 2011 Jun;67(6):1471-8. Epub 2011 Apr 6., [PMID:21468756]
Abstract [show]
PURPOSE: This exploratory study aimed to explain the interindividual variabilities of docetaxel pharmacokinetics and pharmacodynamics in Asian nasopharyngeal carcinoma patients (n = 54) through the genotyping of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 genes. METHODS: Docetaxel was administered over 1 h on days 1, 8, and 15 every 28 days at 30 mg/m(2)/dose. Genomic DNA was isolated from peripheral blood and genotyped for the selected polymorphisms in the candidate genes. Docetaxel pharmacokinetic parameters were estimated by non-compartmental modelling. RESULTS: Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 (IVS12-5676A > G) had significantly higher area under the plasma concentration-time curve of docetaxel (P = 0.026) and lower clearance (P = 0.036) compared to patients with AA/AG genotypes. Patients harbouring the heterozygous genotype (GA + GT + TA) for ABCB1 rs2032582 (2677G > T/A) had the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with GG/TT genotypes (P = 0.006). Similar trend was observed for ABCB1 rs1045642 (3435C > T) with heterozygotes (CT) having the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with CC/TT genotypes (P = 0.066). CONCLUSIONS: This study suggests that the cooperative influence of functional polymorphisms in SLCO1B3 and ABCB1 genes may be responsible for the interindividual variability in docetaxel disposition in Asian nasopharyngeal cancer patients.
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62 AUC0-inf, area under plasma concentration-time curve from time zero to infinity; CL plasma clearance (Whiskers: 5-95 percentile) Table 1 Allele frequencies of CYP3A4, CYP3A5, ABCC2, ABCG2 and SLCO1B3 in healthy Asian populations, NPC patients and comparisons with Caucasians SNPs rs ID Allele Allelic frequencies Chinese Malays Indians Caucasians NPC patients CYP3A4 (UCSC accession number NM_017460) CYP3A4*1B rs2740574 A 1 1 1 0.98 1 G 0 0 0 0.02 0 IVS6-191C [ T rs35599367 C 1 1 1 0.95 [2] 1 T 0 0 0 0.05 0 CYP3A5 (Ensembl gene ID ENSG00000106258) CYP3A5*3 rs776746 A 0.24 0.39 0.41 0.15 [7] 0.33 G 0.76 0.61 0.59 0.85 0.67 CYP3A5*6 rs10264272 G 1 1 1 1 [7] 1 A 0 0 0 0 0 ABCB1 (UCSC accession number NM_000927) 1236C [ T rs1128503 C 0.28 0.34 0.33 0.59 [15] 0.36 T 0.72 0.66 0.67 0.41 0.64 2677G [ A/T rs2032582 G 0.38 0.53 0.33 0.56 [15] 0.51 (Ala893Ser/Thr) A 0.12 0.03 0.07 0.02 0.10 T 0.5 0.44 0.6 0.42 0.39 3435C [ T rs1045642 C 0.47 0.49 0.63 0.46 [15] 0.66 T 0.53 0.51 0.37 0.54 0.34 ABCC2 (UCSC accession number NM_000392) *?9383C [ G rs12762549 C 0.4 0.4 0.55 NA 0.40 G 0.6 0.6 0.45 NA 0.60 ABCG2 (UCSC accession number NM_004827) 421C [ A rs2231142 C 0.72 [25] 0.73 [25] 0.85 [25] 0.88 [16] 0.71 (Gly141Lys) A 0.28 0.27 0.15 0.12 0.29 SLCO1B3 (UCSC accession number NM_019844) 334T [ G rs4149117 T 0.35 0.2 0.08 0.15 [14] (Ser112Ala) G 0.65 0.8 0.92 0.86 439A [ G rs57585902 A 1 1 1 0.995 [14] 1 (Thr147Ala) G 0 0 0 0.005 0 699G [ A rs7311358 G 0.36 0.19 0.1 0.16 [14] 0.24 (Met233Ile) A 0.64 0.81 0.9 0.84 0.76 767G [ C rs60140950 G 1 0.96 0.95 0.81 [14] 1 (Gly256Ala) C 0 0.04 0.05 0.19 0 1559A [ C NA A 1 1 1 1 [14] 1 (His520Pro) C 0 0 0 0 0 1564G [ T rs72559743 G 1 1 1 0.98 [5] 1 (Gly522Cys) T 0 0 0 0.02 0 1679T [ C rs12299012 T 1 1 1 0.98 [14] 1 (Val560Ala) C 0 0 0 0.02 0 IVS12-5676A [ G rs11045585 A 0.82 0.82 0.97 NA 0.78 G 0.18 0.18 0.03 NA 0.22 NA not available The genotype and allele frequencies of CYP3A4*1B, CYP3A5*3, ABCB1 1236C [ T, 2677G [ T/A, 3435C [ T in healthy Asian subjects are available in the previous publication [11] nadir haemoglobin from cycle 1 baseline compared to those with GG (n = 14) or TT (n = 8) genotypes [median (range); percentage decrease in nadir haemoglobin from cycle 1 baseline (%); GA ?
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ABCB1 p.Gly141Lys 21468756:62:1212
status: NEW