Vol. 31, Issue 5, 677-680, May 2003

Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy

Takeshi Hirota, Ichiro Ieiri, Hiroshi Takane, Hiroyuki Sano, Katsuyuki Kawamoto, Hironao Aono, Akira Yamasaki, Hiromi Takeuchi, Mikio Masada, Eiji Shimizu, Shun Higuchi, and Kenji Otsubo

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka (T.H., S.H.); Department of Hospital Pharmacy (I.I., H.T., K.O.), Third Department of Internal Medicine (H.S., A.Y., E.S.), and Oto-Rhino-Laryngology (K.K., H.T.), Faculty of Medicine, Tottori University, Yonago; and Department of Hospital Pharmacy, Fukui Medical University, Fukui (H.A., M.M.), Japan

In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and µ opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.