Abstract
The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C>T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus, we evaluated the role of I399C>T in SN-38 glucuronidation using 177 Japanese cancer patients administered irinotecan. I399C>T was detected at a 0.636 allele frequency. This polymorphism was in strong linkage disequilibrium (LD) with UGT1A9*1b (–126_–118T9>T10, |D′| = 0.99) and UGT1A1*6 (211G>A, 0.86), in moderate LD with UGT1A1*60 (–3279T>G, 0.55), but weakly associated with UGT1A1*28 (–54_–39A(TA)6TAA>A(TA)7TAA, 0.25). Haplotype analysis showed that 98% of the I399C alleles were linked with low-activity haplotypes, either UGT1A1*6, *28, or *60. On the other hand, 85% of the T alleles were linked with the UGT1A1 wild-type haplotype *1. Although I399T-dependent increases in SN-38 glucuronide/SN-38 area under concentration-time curve (AUC) ratio (an in vivo marker for UGT1A activity) and decreases in SN-38 AUC/dose were apparent (P < 0.0001), these effects were no longer observed after stratified patients by UGT1A1*6, *28, or *60 haplotype. Thus, at least in Japanese populations, influence of I399C>T on SN-38 glucuronidation is attributable to its close association with either UGT1A1*6, *28, or *60.
Footnotes
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This study was supported in part by the program for the Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation [Grant 05-25]; and a Health and Labour Sciences Research grant from the Ministry of Health, Labour and Welfare in Japan [Grant KHB1008].
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Y.S. and K.S. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.024208.
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ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; UGT, UDP-glucuronosyltransferase; SNP, single nucleotide polymorphism; SN-38G, SN-38 glucuronide; AUC, area under concentration-time curve; I399, UGT1A9 IVS1+399; LD, linkage disequilibrium.
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↵1 Current affiliation: Department of Medical Oncology, Oita University Faculty of Medicine, Yufu, Japan.
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↵2 Current affiliation: Medical Oncology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Kobe, Japan.
- Received August 26, 2008.
- Accepted October 30, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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