Effect of D256N and Y483D on Propofol Glucuronidation by Human Uridine 5′-diphosphate Glucuronosyltransferase (UGT1A9)
Hiroko Takahashi, Yoshihiro Maruo, Asami Mori, Masaru Iwai, Hiroshi Sato,
Yoshihiro Takeuchi,
Hiroshi Sato
Bioscience, Shiga University of Medical Science, Shiga, Japan
Search for more papers by this authorHiroko Takahashi, Yoshihiro Maruo, Asami Mori, Masaru Iwai, Hiroshi Sato,
Yoshihiro Takeuchi,
Hiroshi Sato
Bioscience, Shiga University of Medical Science, Shiga, Japan
Search for more papers by this authorAuthor for correspondence: Yoshihiro Maruo, Department of Pediatrics, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Shiga 520-2192, Japan (fax +81-77-548-2230, e-mail [email protected]).
Abstract
Abstract: Uridine 5′-diphosphate glucuronosyltransferases (UGTs) are part of a major elimination pathway for endobiotics and xenobiotics. UGT1A9 is a UGT that catalyses the conjugation of endogenous oestrogenic and thyroid hormones, acetaminophen, SN-38 (an active metabolite of irinotecan) and phenols. UGT1A9 is the only isoform that catalyses the glucuronidation of propofol (2,6-diisopropylphenol) in the liver. In the present study, we analysed polymorphisms of UGT1A9 in 100 healthy adult Japanese volunteers. A transversion of 766G > A resulting in the amino acid substitution of D256N was detected in exon 1. The allele frequency of D256N is 0.005. We investigated the effects of D256N and Y483D, which is located on the common exon of UGT1, on propofol glucuronidation by an in vitro expression study. The Km of wild-type, D256N and Y483D for propofol glucuronidation were 111.2, 43.6 and 64.5 µM, respectively. The Vmax of D256N and Y483D were 8.1% and 28.8%, and the efficiencies (Vmax/Km) were 19.1% and 57.1% of the wild-type, respectively. For mycophenolic acid, 1-naphthol and naringenin, the D256N variant lowered glucuronidation activity considerably, compared to Y483D. The Vmax value of D256N variant for mycophenolic acid was only 9.5% of the wild-type. This study shows the importance of D256N in differences between individuals concerning adverse effects of drugs that are catalysed primarily by UGT1A9. Carriers of D256N may be at risk of suffering adverse effects of propofol and other substrates that are primarily metabolized by UGT1A9.
References
- 1 Mackenzie PI, Walter Bock K, Burchell B, Guillemette C, Ikushiro S, Iyanagi T et al . Nomenclature update for the mammalian UDP-glucuronosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 2005; 15: 677–85.
- 2 Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK et al . Thirteen UDP glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 2001; 11: 357–68.
- 3 Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT et al . A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem 1992; 267: 3257–61.
- 4 Strassburg CP, Manns MP, Tukey RH. Expression of the UDP-glucuronosyltransferase 1A locus in human colon. J Biol Chem 1998; 273: 8719–26.
- 5 Findlay KA, Kaptein E, Visser TJ, Burchell B. Characterization of the uridine diphosphate-glucuronosyltransferase-catalyzing thyroid hormone glucuronidation in man. J Clin Endocrinol Metab 2000; 85: 2879–83.
- 6 Court MH, Duan SX, Von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO et al . Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 2001; 299: 998–1006.
- 7 Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C. Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002; 62: 608–17.
- 8 Ebner T, Burchell B. Substrate specificities of two stably expressed human liver UDP-glucuronosyltransferases of the UGT1 gene family. Drug Metab Dispos 1993; 21: 50–55.
- 9 Wooster R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B. Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family. Biochem J 1991; 278: 465–9.
- 10 Albert C, Vallee M, Beaudry G, Belanger A, Hum DW. The monkey and human uridine diphosphate-glucuronosyltransferase UGT1A9, expressed in steroid target tissues, are estrogen-conjugating enzymes. Endocrinology 1999; 140: 3292–302.
- 11 AI-Jahdari WS, Yamamoto K, Hiraoka H, Nakamura K, Goto F, Horiuch R. Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver. Eur J Clin Pharmacol 2006; 62: 527–33.
- 12 Maruo Y, Iwai M, Mori A, Sato H, Takeuchi Y. Polymorphism of UDP-glucuronosyltransferase and drug metabolism. Curr Drug Metab 2005; 6: 91–9.
- 13 Iwai M, Maruo Y, Ito M, Yamamoto K, Sato H, Takeuchi Y. Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity. J Human Genetics 2004; 49: 123–8.
- 14 Mori A, Maruo Y, Iwai M, Sato H, Takeuch Y. UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos 2005; 33: 672–5.
- 15
Simons PJ,
Cockshott ID,
Douglas EJ,
Gordon EA,
Hopkins K,
Rowland M.
Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol.
Xenobiotica
1998; 18: 429–40.
10.3109/00498258809041679 Google Scholar
- 16 Court MH. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases. Methods Enzymol 2005; 400: 104–16.
- 17 King CD, Rios GR, Green MD, Tephly TR. UDP-glucuronosyltransferases. Curr Drug Metab 2000; 1: 143–61.
- 18 Mano Y, Usui T, Kamimura H. Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol 2007; 101: 211–4
- 19 Wolf AR, Potter F. Propofol infusion in children: when does an anesthetic tool become an intensive care liability? Paediatr Anaesth 2004; 14: 435–8.
- 20 Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ et al . Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992; 5: 613–6.
- 21 Kato S, Hiura H, Kisaki O, Samori T, Sato H. Gene frequencies of G71R, TA(TA)7TAA and Y486D of UDP-glucuronosyltransferase (UGT1A1). Rinsho Byori 2006; 54 (Suppl.): 151.
- 22 Yamamoto K, Sato H, Fujiyama Y, Doida Y, Bamba T. Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler–Najjar syndrome type II. Biochim Biophys Acta 1998; 1406: 267–73.
- 23 Jinno H, Tanaka-Kagawa T, Hanioka N, Saeki M, Ishida S, Nishimura T et al . Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, and Y486D. Drug Metab Dispos 2003; 31: 108–13.
- 24 Ito M, Yamamoto K, Maruo Y, Sato H, Fujiyama Y, Bamba T. Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide. Eur J Clin Pharmacol 2002; 58: 11–4.
- 25 Kurkela M, Hirvonen J, Kostiainen R, Finel M. The interactions between the N-terminal and C-terminal domains of the human UDP-glucuronosyltransferases are partly isoform-specific, and may involve both monomers. Biochem Pharmacol 2004; 68: 2443–50.
- 26 Kraemer D, Klinker H. Crigler–Najjar syndrome type II in a Caucasian patient resulting from two mutations in the bilirubin uridine 5′-diphosphate-glucuronosyltransferase (UGT1A1) gene. J Hepatol 2002; 36: 706–7.
- 27 Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K et al . Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. J Pharmacol Exp Ther 2003; 306: 688–93.
- 28 Bosma PJ, Chowdhury JR, Bakker C, Gantla S, De Boer A, Oostra BA et al . The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1in Gilbert's syndrome. N Engl J Med 1995; 333: 1171–5.
- 29 Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996; 347: 578–81.
- 30 Sato H, Adachi Y, Koiwai O. The genetic basis of Gilbert's syndrome. Lancet 1996; 347: 557–8.
- 31 Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatrics 1999; 103: 1224–7.
- 32 Maruo Y, Nishizawa K, Sato H, Sawa H, Shimada M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics 2000; 55: 126–32.
- 33 Villeneuve L, Girard H, Fortier LC, Gagne JF, Guillemette C. Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 2003; 307: 117–28.
- 34 Thibaudeau J, Lepine J, Tojcic J, Duguay Y, Pelletier G, Plante M et al . Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Cancer Res 2006; 66: 125–33.
- 35 Paoluzzi L, Singh AS, Price DK, Danesi R, Mathijssen RH, Verweij J et al . Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. J Clin Pharmacol 2004; 44: 854–60.
- 36 Fujita K, Ando Y, Nagashima F, Yamamo, A-Y, Endo H, Kodama K et al . Novel single nucleotide polymorphism of UGT1A9 gene in Japanese. Drug Metab Pharmacokinet 2006; 21: 79–81.
- 37 Mehlotra RK, Bockarie MJ, Zimmerman PA. Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations. Eur J Clin Pharmacol 2007; 63: 1–8.
- 38 Aono S, Yamada Y, Keino H, Hanada N, Nakagawa T, Sasaoka Y et al . Identification of defect in the genes for bilirubin UDP-glucuronosyltransferase in a patient with Crigler-Najjar syndrome type II. Biochem Biophys Res Commun 1993; 197: 1239–44.
- 39 Maruo Y, Sato H, Yamano T, Doida Y, Shimada M. Gilbert syndrome caused by a homozygous missense mutation (Tyr486Asp) of bilirubin UDP-glucuronosyltransferase gene. J Pediatr 1998; 132: 1045–7.
- 40 Yamamoto K, Soeda Y, Kamisako Y, Hosaka H, Fukano M, Sato H et al . Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler–Najjar syndrome type II. J Hum Genet 1998; 43: 111–4.
- 41 Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 2004; 32: 775–8.
Citing Literature
