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Biomedical subjects

Yoshihiro Maruo

Publications and source records attributed to Yoshihiro Maruo.

13 recordsLinked to original sources
PubMed2006

Liver transplantation using donors with Gilbert syndrome.

Serum bilirubin level is an essential factor included in the first step in evaluating living liver donor candidates. Our evaluation strategy was examined in living donors with possible Gilbert's syndrome (GS). When donor candidates had hyperbilirubinemia (>1.5 mg/dl), but otherwise normal liver function tests, their genomic DNA was isolated from leukocytes. They were diagnosed with GS when they had mutations of uridine diphosphate glucuronosyltransferase 1 typical to GS. The donors and recipients were divided into two groups: GS donors and their recipients (n = 6, each) and non-GS donors and their recipients (n = 65). All GS donors and their recipients had an unremarkable postoperative course. Total bilirubin levels of the recipients of GS donors were higher than those of recipients of non-GS donors. Living donor liver transplantation is safe for both donors with GS and their recipients.

Bilirubin↗
PubMed2005

UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation.

The UDP-glucuronosyltransferase (UGT) family plays a major role in the excretion of endobiotics and xenobiotics and their metabolites. Human UGT1A4 catalyzes the glucuronidation of primary, secondary, and tertiary amines, sapogenins, androgens, and progestins. We directly sequenced polymerase chain reaction-amplified fragments of the UGT1A4 gene from 100 healthy adult Japanese volunteers and calculated their mutation frequency. We identified four single nucleotide polymorphisms (SNPs): three in exon 1 (142T > G: L48V, 448T > C: L150L, 804G > A: P268P), and one in intron 1 (867 + 43C > T). We found three types of alleles with distinct SNP combinations that coded for different amino acid sequences: L48V-L150L-P268P-867 + 43C > T (frequency, 0.155), L48V (0.01), and P268P (0.01) (wild-type frequency was 0.825). The L48V mutant gave twice the efficiency (V(max)/K(m)) for the antipsychotic drug clozapine as the wild-type. Efficiencies of L48V for trans-androsterone, imipramine, and cyproheptadine were increased, but the efficiency for tigogenin was reduced. L48V therefore increased or decreased the glucuronidation activity, depending upon the substrates. This study shows the importance of identifying patients with the L48V polymorphism when calculating dosage, and when considering the potential adverse effects of drugs that are substrates of UGT1A4.

Alleles↗
PubMed2005

Polymorphism of UDP-glucuronosyltransferase and drug metabolism.

UDP-glucuronosyltransferase is a group of catabolic enzymes involved in the detoxification and excretion of many xenobiotic and endogeneous substances in intrahepatic and extrahepatic tissues. The group consists of two subfamilies, UGT1 and UGT2. UGT1 consists of 5 exons and has a unique gene structure. There are thirteen exon 1s from UGT1A1 to UGT1A13P, and exon 2 to exon 5 are used in common for all mRNAs expressed from the gene. Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity. In contrast, the genes of the UGT2 family consist of 6 exons, and all the enzymes have an individual set of exon 1 to exon 6. In UGT1 there are no reports of polymorphism in the common exons, although a number of polymorphisms have been reported for exon 1s. The mutations of UGT1A1 cause hereditary unconjugated hyperbilirubinemias: Crigler-Najjar syndrome type I, type II and Gilbert syndrome. UGT1A1 has two major polymorphisms--a missense mutation of G71R and an insertion mutation of TATA box. Prevalence of Gilbert syndrome is attributed to these polymorphisms. Since UGT1A1 metabolizes not only bilirubin but also hormones and drugs, the mutations could be involved in carcinogenesis and adverse drug reactions. Recent studies also revealed a widespread presence of diverse polymorphisms in other isoforms of UGT1 as well as the UGT2 family, including UGT1A6, UGTG1A7, UGT1A8, UGT1A10, UGT2B4, UGT2B7 and UGT2B15. The incidences and types of the polymorphisms for these enzymes are quite different in region and ethnic groups. Understanding of these polymorphisms is essential for the prevention of adverse effects of a considerable number of drugs and to predict cancer risks.

Animals↗
PubMed2004

Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome.

Gilbert syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The mutation, A(TA)7TAA, is thought to be the sole cause of the syndrome in Caucasians, but an enhancer polymorphism (T-3279G) that lowers transcriptional activity has recently been reported. We have tested the linkage of the two mutations in 11 Caucasians and 12 Japanese patients who were homozygous for A(TA)7TAA. All 23 patients were also homozygous for T-3279G, indicating that T-3279G and A(TA)7TAA were linked. The decrease in transcription caused by both mutations together may be essential to the syndrome.

Asian People↗
PubMed2004

A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone.

Specific inhibitors of hyaluronan (HA) biosynthesis can be valuable therapeutic agents to prevent cancer invasion and metastasis. We have found previously that 4-methylumbelliferone (MU) inhibits HA synthesis in human skin fibroblasts and in group C Streptococcus. In this paper, the inhibition mechanism in mammalian cells was investigated using rat 3Y1 fibroblasts stably expressing HA synthase (HAS) 2. Exposure of the transfectants to the inhibitor resulted in significant reduction of HA biosynthesis and matrix formation. The evaluation of HAS transcripts and analysis of cell-free HA synthesis demonstrated the post-transcriptional suppression of HAS activity by MU. Most interesting, the post-transcriptional suppression of HAS activity was also observed using p-nitrophenol, a well known substrate for UDP-glucuronyltransferases (UGT). We investigated whether the inhibition was exerted by the glucuronidation of MU using both high pressure liquid chromatography and TLC analyses. The production of MU-glucuronic acid (GlcUA) was consistent with the inhibition of HA synthesis in HAS transfectants. MU-GlcUA was also detected at a similar level in control cells, suggesting that the glucuronidation was mediated by an endogenous UGT. Elevated levels of UGT significantly enhanced the inhibitory effects of MU. In contrast, the inhibition by MU was diminished to the control level when an excess of UDP-GlcUA was added to the cell-free HA synthesis system. We propose a novel mechanism for the MU-mediated inhibition of HA synthesis involving the glucuronidation of MU by endogenous UGT resulting in a depletion of UDP-GlcUA.

Animals↗
PubMed2004

Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity.

Human UDP-glucuronosyltransferase (UGT) is a part of a major excretion pathway for endobiotics and xenobiotics. The UGT family of genes is highly polymorphic, and our aim is to describe novel polymorphisms at the UGT1A3 locus and determine how they alter substrate metabolism and drug reactions. One hundred healthy Japanese adults volunteered for the present study. We sequenced PCR-amplified fragments of the gene directly, and calculated the frequency of the genetic variations detected. To measure variant enzyme activity, we constructed five expression models and used estrone as the substrate in the assays. We identified six novel single nucleotide polymorphisms (SNPs). Of these, four caused amino acid substitutions (17A-->G: Q6R, 31T-->C: W11R, 133C-->T: R45W, and 140T-->C: V47A) and the remaining two were silent (81G-->A: E27E and 447A-->G: A159A). We found five types of alleles having differing SNP combinations: wild type (frequency=0.61), W11R-E27E-A159A (0.10), Q6A-W11R-E27E-A159A (0.055), W11R-E27E-V47A-A159A (0.125), and R45W (0.11). Expression studies found that the variants changed the enzyme efficiencies ( Km/ Vmax) to 121% of the wild type for W11R, 86% for Q6R-W11R, 369% for W11R-V47A, and 70% for R45W. Several UGT 1A3 polymorphisms exist in the Japanese population, having different levels of activity. These polymorphisms are capable of affecting the steady state levels of estrogens, and may increase sensitivity to adverse drug effects.

Alleles↗
PubMed2004

Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects.

BACKGROUND AND AIM: Numerous mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with familial unconjugated hyperbilirubinemia. The UGT1A1 mutation appears to be considerably different among ethnic groups. To clarify the incidence of this gene mutation in the Japanese population, the presence of UGT1A1 mutation was investigated in a group of Japanese patients with Crigler-Najjar syndrome type 2 (CNS2) and Gilbert's syndrome (GS), as well as in healthy anicteric subjects. METHODS: Four patients with CNS2, 63 patients with GS, and 71 healthy subjects were enrolled in the study. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. The PCR products were directly sequenced by a dye terminating method. The UGT1A1 enzyme activity was determined in COS7 cells transfected with wild or P364L (1091 C > T) mutant DNA. RESULTS: Homozygous Y486D was observed in all four patients with CNS2. The GS patients had UGT1A1 mutations with 13 different genotypes in the promoter and coding region. Homozygous TA insertion in the TATA box (TA7) of the promoter region (TA7/7; 33%), homozygous G71R (9%), and combination of TA7/6 and heterozygous G71R (17%) were the most frequent findings in GS patients. Homozygous or heterozygous Y486D (8%) and P229Q (8%) were also observed in GS. A novel mutation, heterozygous P364L, was also identified in a GS patient. In addition to GS patients, homozygous or heterozygous TA7, G71R, and heterozygous Y486D were also observed in healthy subjects. The allele frequency of G71R and TA7 was 0.183 and 0.113 in healthy subjects, respectively. The P364L UGT1A1 enzyme activity was 64.4% lower than the wild-type enzyme activity. CONCLUSIONS: Polymorphisms in the coding region of UGT1A1 were commonly observed in Japanese patients with GS and in healthy subjects. The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations.

Adult↗
PubMed2003

A pediatric patient with sporadic dentatorubral pallidoluysian atrophy.

We report a 10-year-old girl with the juvenile type of dentatorubral pallidoluysian atrophy. There were no affected family members, suggesting a sporadic case. Deoxyribonucleic acid analysis for the dentatorubral pallidoluysian atrophy gene was performed, and the CAG trinucleotide repeat numbers in this patient were 61/15. Gene analysis of the patient's parents was not performed. The molecular mechanisms of the occurrence of sporadic cases have not been clarified.

Adult↗
PubMed2002

Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide.

OBJECTIVE: We investigated how the conserved mutation (Y486D) changed the kinetic parameters of uridine diphosphate glucuronosyltransferase 1A1 and 1A6 (UGT1A1 and 1A6) for 2-amino-5-nitro-4-trifluoromethylphenol, which is a major metabolite of flutamide, a nonsteroidal antiandrogenic agent. METHODS: The wild-type or mutant cDNA-expressed UGT was co-incubated with 2-amino-5-nitro-4-trifluoromethylphenol (aglycone) and uridine diphosphate-glucuronic acid (UDP-GA, donor substrate). The glucuronidation of the aglycone was determined. RESULTS: The maximum velocities of the mutant UGT1A1 and UGT1A6 were about 12% and less than 1% of the corresponding wild-type, respectively. The Michaelis constant (K(M)) for the aglycone of the wild-type UGT1A1 was double that of the mutant, but the K(M) for UDP-GA of the wild-type UGT1A1 was not significantly different from that of the mutant. CONCLUSION: Patients with Y486D may accumulate excessive 2-amino-5-nitro-4-trifluoromethylphenol, which might lead to unexpected toxicity.

Androgen Antagonists↗
PubMed2002

[UDP-glucuronosyltransferase].

UDP-glucuronosyltransferases (UGTs) represent a family of enzymes that glucuronidate many internal substances and drugs. This family acts as a drug metabolism phase II reactor in the liver and comprises one of the major protective mechanisms from toxic chemical substances. UGTs have two subfamilies; UGT1 and UGT2. UGT1 gene expresses 12 isoforms which are produced from a single gene by alternative splicing of a primary transcript. Each isoform has specific substrates. UGT1A1 conjugates bilirubin, and mutations of the gene cause hereditary unconjugated hyperbilirubinemias (Crigler-Najjar syndrome and Gilbert's syndrome). Recently, polymorphisms of UGT1A1 were revealed. In the Japanese population, there is a polymorphism of G71R and this mutation is a risk factor of neonatal hyperbiliruibnemia and a genetic cause of breast milk jaundice. These polymorphisms of UGTs might contribute to individual variations of drug metabolism and toxicity as well as inherited diseases.

Glucuronosyltransferase↗