Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients.
We have screened a cohort of 239 Norwegian cancer patients for sequence variation in the coding and regulatory regions of the UDP-glucuronosyltransferase 2B7 gene (UGT2B7) and analyzed the impact of gene variants on morphine glucuronidation in vivo. In all, 12 single nucleotide polymorphisms (SNPs) were identified, 10 of which have not been previously described. Only one SNP causes a change in amino acid sequence (H268Y). Seven UGT2B7 genotypes were observed and three main haplotypes predicted. There was no correlation between UGT2B7 genotype or haplotype and morphine glucuronide to morphine serum ratios among 175 patients who received chronic oral morphine therapy, and who had normal renal and hepatic function. The apparent lack of functional polymorphisms fits well with the near unimodal, but broad, distributions of the ratios (morphine 3-glucuronide/morphine: 6.4-309.2; morphine 6-glucuronide/morphine: 0.5-72.8). Our results suggest that factors other than UGT2B7 polymorphism may be more deciding for the variability in morphine glucuronide to morphine serum ratios.
Holthe
M
M
Institute of Cancer Research and Molecular Biology, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Rakvåg
T N
TN
Klepstad
P
P
Idle
J R
JR
Kaasa
S
S
Krokan
H E
HE
Skorpen
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009020:Morphine / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D014407:Tumor Cells, Cultured
D020719:Glucuronides; D009020:Morphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase