Share This Article:

Bucolome N-Glucuronide Formation: Species Differences and Identification of Human UDP-Glucuronosyltransferase Isoforms

Abstract Full-Text HTML Download Download as PDF (Size:172KB) PP. 361-369
DOI: 10.4236/pp.2011.24047    3,554 Downloads   7,309 Views  

ABSTRACT

The barbituric acid derivative bucolome (BCP) is a nonsteroidal anti-inflammatory drug. The present study investigated whether BCP N-glucuronide (BCP-NG, the primary metabolite of BCP) was produced in mammalian species other than rats, and attempted to identify the UDP-glucuronosyltransferase (UGT) isoform (s) responsible for formation of BCP-NG in humans. BCP-NG was detected in all species tested. The results were as follows (pmol equivalent/ min/mg protein): rat, 479 ± 83; Mongolian gerbil, 378 ± 9; rabbit, 275 ±26; guinea pig, 257 ± 10; human, 242 ± 18; hamster, 177 ± 22; and mouse, 167 ± 15. Since human liver microsomes formed BCP-NG, we investigated the metabolites of BCP excreted in the urine of a patient after oral administration of BCP (600 mg). BCP and BCP-NG were excreted in the urine at amounts of 2.9 mg (about 0.5% of the dose) and 14.4 mg (about 2.5% of the dose) over 12 hours. In order to identify the UGT isoforms involved in formation of BCP-NG in humans, we investigated BCP-NG formation by the microsomes of insect cells expressing each of twelve UGT isoforms (hUGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17). As a result, BCP-NG formation (pmol equivalents/min/mg protein) was observed with microsomes expressing hUGT1A1 (142), 1A3 (196), 1A4 (8), 1A7 (8), 1A8 (66), 1A9 (38), 1A10 (9), 2B4 (7) and 2B7 (16). In particular, the activity of hUGT1A1 and 1A3 was high. These results suggest that the UGT isoforms responsible for formation of BCP-NG exist in various mammalian species, including humans, and that the UGT 1A family is primarily responsible for BCP N-glucuronide formation in humans.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

H. Kanoh, M. Tada, Y. Uesawa and K. Mohri, "Bucolome N-Glucuronide Formation: Species Differences and Identification of Human UDP-Glucuronosyltransferase Isoforms," Pharmacology & Pharmacy, Vol. 2 No. 4, 2011, pp. 361-369. doi: 10.4236/pp.2011.24047.

References

[1] C. Guillemette, “Pharmacogenomics of human UDP- glucuronosyltransferase enzymes,” Pharmacogenomics J, Vol. 3, No. 3, 2003, pp. 136-158.
[2] S. Senda, H. Izumi and H. Fujimura, “On uracil derivatives and related compounds. 6, 5-alkyl-2,4,6-trioxoper- hydrophyrimidine derivatives as antiphlogistics,” Arzneimittel-forschung, Vol. 17, No. 12, 1967, pp. 1519- 1523.
[3] K. Kitani, S. Tsuruoka, R. Miura and Y. Morita, “The effect of bucolome on the canalicular bile formation and sulfobromophthalein transport maximum in the dog,” Biochem Pharmacol, Vol. 25, No. 12, 1976, pp. 1377- 1381.
[4] K. Kitani, M. Nokubo, S. Kanai, R. Miura and T. Uesugi, “The biliary excretion of bucolome in the rat: a possible cause for choleresis,” Biochem Pharmacol, Vol. 26, No. 24, 1977, pp. 2457-2461.
[5] T. Yashiki, T. Matsuzawa, T. Kondo, Y. Uda and T. Shima, “Studies on the metabolic fate and the pharmacokinetics of 5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhy- dropyrimidine (BCP) in man. I. Identification of the metabolites of BCP in human urine,” Chem Pharm Bull, Vol. 19, No. 3, 1971, pp. 468-477.
[6] M. Kobayashi, M. Takagi, K. Fukumoto, R. Kato, K.Tanaka and K. Ueno, “The effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan,” Drug Metab Pharmacokinet, Vol. 23, No. 2, 2008, pp. 115-119.
[7] H. Takahashi, T. Kashima, S. Kimura, N. Murata, T. Takaba, K. Iwade, T. Abe, H. Tainaka, T. Yasumori and H. Echizen, “Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: application of In vitro approaches to predicting In vivo reduction of (S) warfarin clearance,” Drug Metab Dispos, Vol. 27, No. 10, 1999, pp. 1179-1186.
[8] T. Yashiki, T. Kondo, Y. Uda and H. Mima, “Studies on the metabolic fate and the pharmacokinetics of 5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine (BCP) in man. II. Determination of BCP and its metabolite, 1-cyclohexyl-5-(3-hydroxybutyl)-2,4,6-trioxoperhydropyrimidine by ultraviolet absorption method,” Chem Pharm Bull, Vol. 19, No. 3, 1971, pp. 478-486.
[9] T. Yashiki, Y. Uda, T. Kondo and H. Mima, “Studies on the metabolic fate and the pharmacokinetics of 5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine (BCP) in man. III. Gas-liquid chromatographic determination of BCP and its metabolites,” Chem Pharm Bull, Vol. 19, No. 3, 1971, pp. 487-492.
[10] T. Yashiki, T. Matsuzawa, M. Yamada, T. Kondo and Y. Uda, “Studies on the metabolic fate and the pharmacokinetics of 5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydro- pyrimidine (BCP) in man. IV. Pharmacokinetics of BCP in man following oral administration,” Chem Pharm Bull, Vol. 19, No. 5, 1971, pp. 869-880.
[11] T. Yashiki, T. Matsuzawa, M. Yamada, T. Kondo, H. Mima, M. Yamamoto, T. Yamada, M. Nakajima and K. Doi, “Studies on the metabolic fate and the pharmacokinetics of 5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydro- pyrimidine (BCP) in man. V. Pharmacokinetics of BCP in man and in rabbit following intravenous administration of BCPNa,” Chem Pharm Bul, Vol. 19, No. 5, 1971, pp. 881-891.
[12] BK. Tang, W. Kalow and AA. Grey, “Amobarbital metabolism in man: N-glucoside formation,” Res Commun Chem Pathol Pharmacol, Vol. 21, No. 1, 1978, pp. 45-53.
[13] BK. Tang, W. Kalow and AA. Grey, “Metabolic Fate of Phenobarbital in man N-Glucoside Formation,” Drug Metab Dispos, Vol. 7, No. 5, 1979, pp. 315-318.
[14] K. Mohri, T. Uesugi and K. Kamisaka, “Bucolome N-glucuronide: purification and identification of a major metabolite of bucolome in rat bile,” Xenobiotica, Vol. 15, No. 7, 1985, pp. 615-621.
[15] K. Mohri, Y. Uesawa and T. Uesugi, “Metabolisme of bucolome in rats stability and biliary excretion of bucolome N-glucuronide,” J Chromatogr B Biomed Sci, Vol. 759, No. 1, 2001, pp. 153-159.
[16] OH. Lowry, NJ. Rosebrough, AL. Farr and RJ. Randall, “Protein measurement with the folin phenol reagent,” J Biol Chem, Vol. 193, No. 1, 1951, pp. 265-275.
[17] H. Scheffe, “The Analysis of Variance” John Wiley & Sons Inc, New York, 1959.
[18] S. Kaivosaari, P. Toivonen, LM. Hesse, M. Koskinen, MH. Court and M. Finel, “Nicotine glucuronidation and the human UDPglucuronosyltransferase UGT2B10,” Mol. Pharmacol., Vol. 72, No. 3, 2007, pp. 761-768.
[19] S. Kaivosaari, P. Toivonen, O. Aitio, J. Sipil?, M. Koskinen, JS. Salonen and M. Finel, “Regio- and stereospecific N-glucuronidation of medetomidine: the di%erences between UDP glucuronosyltransferase (UGT) 1A4 and UGT2B10 account for the complex kinetics of human liver microsomes,” Drug Metab. Dispos. Vol. 36, No. 3, 2008, pp. 1529-1537.
[20] S. Kaivosaari, M. Finel and M. Koskinen, “N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases,” Xenobiotica, Vol. 41, No. 8, 2011, pp. 652-659.
[21] BK. Tang, “Drug glucosidation,” Pharmacol Ther, Vol. 46, No. 1, 1990, pp. 53-56.
[22] SG. Paibir and WH. Soine, “High-performance liquid chromatographic analysis of phenobarbital and phenobarbital metabolites in human urine,” J Chromatogr B Biomed Sci, Vol. 691, No. 1, 1997, pp. 111-117.
[23] SM. Neighbors and WH. Soine, “Identification of Phenobarbital N-glucuronides as urinary metabolites of Phenobarbital in mice,” Drug Metab Dispos, Vol. 23, No. 5, 1995, pp. 548-552.
[24] L. Luukkanen, J. Taskinen, M. Kurkela, R. Kostiainen, J. Hirvonen and M. Finel, “Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyl- transferases,” Drug Metab Dispos, Vol. 33, No. 7, 2005, pp. 1017-1026.
[25] S. Ohno and S. Nakajin, “Determination of mRNA Expression of HumanUDP-Glucuronosyltransferases and Application for Localization in Various Human Tissues by Real-Time Reverse Transcriptase-Polymerase Chain Reaction,” Drug Metab Dispos, Vol. 37, No. 1, 2009, pp. 32-40.
[26] T. Zhang, P. Haws, Q. Wu, “Multiple variable first exons: a mechanism for cell- and tissue-specific gene regulation.” Genome Res., Vol. 14, 2004, pp. 79-89.
[27] PI. Mackenzie, KW. Bock, B. Burchell, C. Guillemette, S. Ikushiro, T. Iyanagi, JO. Miners, IS. Owens, DW. Nebert “Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily.” Pharmacogenet. Genomics, Vol. 15, 2005, pp. 677-685.
[28] CD. King, MD. Green, GR. Rios, BL. Coffman, IS. Owens, WP. Bishop and TR. Tephly, “The glucuronidation of exogenous and endogenous compounds by stably expressed rat and human UDP-glucuronosyltransferase 1.1,” Arch. Biochem. Biophys., Vol. 332, No. 1, 1996, pp. 92-100.
[29] JR. Chowdhury, R. Kondapalli and NR. Chowdhury, “Gunn rat: A model for inherited deficiency of bilirubin glucuronidation,” Adv Vet Sci Comp Med, Vol. 37, 1993, pp. 149-173.
[30] H. Kanoh, M. Tada, S. Ikushiro and K. Mohri, “Characterization of Bucolome N-Glucuronide Formation: Tissue specificity and Identification of Rat UDP-Glucuronosyl- transferase Isoform (s),” Pharmacology and Pharmacy, 2011, in press.
[31] H. Kanoh, K. Okada and K. Mohri, “Identification of the UDP-glucuronosyltransferase responsible for bucolome N-glucuronide formation in rats,” Pharmazie, Vol. 65, No. 11, 2010, pp. 840-844.

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.