Summary
The activity of UDP-glucuronosyltransferase (UDPGT) and the concentration of its endogenous substrate, 5′-diphosphoglucuronic acid (UDPGA), have been measured in human liver, kidney, lung and intestinal mucosa.
The activity of UDPGT was tissue- and substrate-dependent. The liver/kidney and liver/intestine ratios for UDPGT varied over one order of magnitude with three substrates. The highest activity of UDGPT in extrahepatic tissues was in the kidney, with 1-naphthol as substrate; it was about half of the hepatic activity.
The concentration (μmol · kg−1) of UDPGA was 279 (liver), 17.4 (kidney), 19.3 (intestinal mucosa) and 17.2 (lung), it was at least 15-fold higher in liver than the other tissues, and the concentration in kidney, lung and intestinal mucosa was similar.
The kinetics of UDPGT in a liver homogenate at varying concentrations of UDPGA and fixed concentration of 1-naphthol, ethinyloestradiol, and morphine was also measured. The apparent kM for UDPGT depended upon the chemical nature of the UDPGA-acceptor substrate; average values of kM were 63, 300, and 700 μmol · 1−1 for 1-naphthol, ethinyloestradiol and morphine respectively. These values are, respectively, lower, similar to and higher than the hepatic concentration of UDPGA.
Under certain circumstances UDPGA may be the limiting factor in the in vivo glucuronidation of drugs by extrahepatic tissues.
Similar content being viewed by others
References
Bock KW, Brunner G, Hoensch H, Huber E, Josting D (1978) Determination of microsomal UDP-glucuronyl transferase in needle biopsy specimens of human liver. Eur J Clin Pharmacol 14: 367–373
Cappiello M, Franchi M, Giuliani L, Pacifici GM (1989) Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3′-phosphate 5′-phosphosulphate in human tissues. Eur J Clin Pharmacol 37: 317–320
Chowdhury JR, Novikoff PM, Chowdhury NR, Novikoff AB (1985) Distribution of UDPG glucuronosyltransferase in rat tissues. Proc Natl Acad Sci USA 82: 2990–2994
Elmamlouk TH, Mukhtar H, Bend JR (1981) The nuclear envelope as a site of glucuronyltransferase in rat liver: properties of and effect of inducers on enzyme activity. J Pharmacol Exp Ther 219: 27–34
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol ragent. J Biol Chem 193: 265–275
Mulder GJ (1982) Conjugation of phenols. In: Jakoby WB, Bend JR, Caldwell J (eds) Metabolic basis of detoxication. Academic Press, New York, pp 248–269
Pacifici GM, Back DJ (1988) Sulphation and glucuronidation of ethinyloestradiol in human liver in vitro. J Ster Biochem 32: 345–349
Pacifici GM, Bencini C, Rane A (1986a) Presystemic glucuronidation of morphine in humans and rhesus monkeys: subcellular distribution of the UDP-glucuronosyltransferase in the liver and intestine. Xenobiotica 16: 123–128
Pacifici GM, Colizzi C, Giuliani L, Rane A (1985) Nuclear and microsomal UDP-glucuronyltransferase in human liver. In: Matern S, Bock KW, Gerok W (eds) Advances in glucuronide conjugation. MTP Press, Lancaster, pp 341–350
Pacifici GM, Franchi M, Bencini C, Repetti F, Di Lascio N, Muraro GB (1988) Tissue distribution of drug metabolizing enzymes. Xenobiotica 18: 849–856
Pacifici GM, Giuliani L, Calcaprina R (1986b) Glucuronidation of 1-naphthol in nuclear and microsomal fractions of the human intestine. Pharmacology 33: 103–109
Park GR, Manara AR, Dawling S (1989) Extra-hepatic metabolism of midazolam. Br J Clin Pharmacol 27: 634–637
Watkins JB, Klaassen CD (1982) Determination of hepatic uridine 5′-diphosphoglucuronic acid concentration by conjugation with diethylstilbestrol. J Pharmacol Meth 7: 145–151
Wong KP (1977) Measurement of nanogram quantities of UDP-glucuronic acid in tissues. Anal Biochem 82: 559–563
Wong KP, Sourkes TL (1967) Determination of UDP and UDPGA in tissues. Anal Biochem 21: 444–453
Zaleski J, Bansal SK, Gessner T (1982) Nuclear membrane-bound UDP-glucuronosyltransferase of rat liver. Can J Biochem 60: 972–979
Zaleski J, Gessner T (1982) Re-investigation of the presence of UDP-glucuronosyltransferase in rat liver mitochondria. Res Commun Chem Pathol Pharmacol 37: 279–291
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cappiello, M., Giuliani, L. & Pacifici, G.M. Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5′-diphosphoglucuronic acid in human tissues. Eur J Clin Pharmacol 41, 345–350 (1991). https://doi.org/10.1007/BF00314965
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00314965