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Variability of human hepatic UDP-glucuronosyltransferase activity

100%

Little J. M., Lester R., Kuipers F., Vonk R., Mackenzie P. I., Drake R. R., Frame L., Radominska-Pandya A.

Acta Biochimica Polonica

1999

tom 46

nr 2

The availability of a unique series of liver samples from human subjects, both control patients (9) and those with liver disease (6; biliary atresia (2), retransplant, chronic tyrosinemia type I, tyrosinemia, Wilson's disease) allowed us to characterize human hepatic UDP-glucuronosyltransferases using photoaffinity labeling, immunoblotting and enzymatic assays. There was wide inter-individual variation in photoincorporation of the photoaffinity analogs, [32]5-azido-UDP-glucuronic acid and [32]5-azido-UDP-glucose and enzymatic glucuronidation of substrates specific to the two subfamilies of UDP-glucuronosyltransferases. However, the largest differences were between subjects with liver disease. Glucuronidation activities toward one substrate from each of the UDP-glucuronosyltransferases subfamilies, 1A and 2B, for control and liver disease, respectively, were 1.7-4.5 vs 0.4-4.7 nmol/mg × min for hyodeoxycholic acid (2B substrate) and 9.2-27.9 vs 8.1-75 nmol/mg × min for p-chloro-m-xylenol (1A substrate). Microsomes from a patient with chronic tyrosinemia (HL32) photoincorporated [32]5-azido-UDP-glucuronic acid at a level 1.5 times higher than the other samples, was intensely photolabeled by [32]5-azido-UDP-glucose and had significantly higher enzymatic activity toward p-chloro-m-xylenol. Immunoblot analysis using anti-UDP-glucuronosyltransferase antibodies demonstrated wide inter-individual variations in UDP-glucuronosyltransferase protein with increased UDP-glucuronosyltransferase protein in HL32 microsomes, corresponding to one of the bands photolabeled by both probes. Detailed investigation of substrate specificity, using substrates representative of both the 1A (bilirubin, 4-nitrophenol) and 2B (androsterone, testosterone) families was carried out with HL32, HL38 (age and sex matched control) and HL18 (older control). Strikingly increased (5-8-fold) glucuronidation activity was seen in comparison to HL18 only with the phenolic substrates. The results indicate that one or more phenol-specific UDP-glucuronosyltransferase 1A isoforms are expressed at above normal levels in this tyrosinemic subject.

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Mechanism of action of 4-hydroxyphenylpyruvate dioxygenase inhibitor herbicide on homoterm animals and humans

63%

Antonenko A. M., Blagaia A. V., Omelchuk S. T., Korshun M. M., Vavrinevych H. P., Milohov D. S., Pelo I. M., Bojar I.

Journal of Pre-Clinical and Clinical Research

2015

tom 09

nr 2

It was found that the main mechanisms of action of 4-hydroxyphenylpyruvatedioxygenase inhibitors are the development of tyrosinemia and alternations in thyroid hormone level as a result of hepatic enzyme induction. The main target organs of its action are the eyes, liver and thyroid gland. It was proved that the most adequate model for extrapolation of the effects of tyrosinemia on humans are mice, because their tyrosine aminotransferase activity level is similar to that in humans.

Ograniczanie wyników

1 Acta Biochimica Polonica

1 Journal of Pre-Clinical and Clinical Research

1 Antonenko A. M.

1 Blagaia A. V.

1 Bojar I.

1 Drake R. R.

1 Frame L.

1 Korshun M. M.

1 Kuipers F.

1 Lester R.

1 Little J. M.

1 Mackenzie P. I.

1 Milohov D. S.

1 Omelchuk S. T.

1 Pelo I. M.

1 Radominska-Pandya A.

1 Vavrinevych H. P.

1 Vonk R.

1 2015

1 1999

Wyniki wyszukiwania

Variability of human hepatic UDP-glucuronosyltransferase activity

Mechanism of action of 4-hydroxyphenylpyruvate dioxygenase inhibitor herbicide on homoterm animals and humans