Classification and genetic expression of Wistar rats with high and low hepatic microsomal UDP-glucuronosyltransferase activity towards androsterone.
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ABSTRACT:
SUBMITTER: Matsui M
PROVIDER: S-EPMC1158087 | biostudies-other | 1982 Jan
REPOSITORIES: biostudies-other
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Project description:Postnatal development of hepatic UDP-glucuronosyltransferase and sulphotransferase activities towards androsterone and 4-nitrophenol as well as cytochrome P-450 contents was studied in male and female Wistar rats. The rats with high and low UDP-glucuronosyltransferase activity towards androsterone were classified by the genotype of the parent animals. UDP-glucuronosyltransferase activity towards androsterone began rapidly to enhance after 30 days of age in the high-activity group, whereas the transferase activity remained low throughout in the low-activity group. Such a striking difference was not observed in UDP-glucuronosyltransferase activity towards 4-nitrophenol, sulphotransferase activity towards androsterone and 4-nitrophenol, and cytochrome P-450 contents. Sex-based difference in the sulphotransferase activity was marked after 30 days of age. Sulphotransferase activity towards androsterone was much higher in adult females than in adult males, whereas higher sulphation activity towards 4-nitrophenol was found in adult males. The results also indicate that the low level of the UDP-glucuronosyltransferase activity did not lead to compensatory stimulation of the sulphotransferase activity.
| S-EPMC1158370 | biostudies-other
Project description:Hepatic microsomal UDP-glucuronosyltransferases towards androsterone and testosterone were purified by chromatofocusing and UDP-hexanolamine affinity chromatography in Wistar rats which had genetic deficiency of androsterone UDP-glucuronosyltransferase activity. In rats with the high-activity phenotype, androsterone (the 3-hydroxy androgen) UDP-glucuronosyltransferase was eluted at about pH 7.4 and had a subunit Mr of 52 000, whereas testosterone (the 17-hydroxy steroid) UDP-glucuronosyltransferase was eluted at about pH 8.4 and had a subunit Mr of 50 000. The transferase that conjugates both androsterone and testosterone was eluted at about pH 8.0, had subunit Mr values of 50 000 and 52 000, and appeared to be an aggregate or hybrid of androsterone and testosterone UDP-glucuronosyltransferases. In rats with the low-activity phenotype, androsterone UDP-glucuronosyltransferase was absent, whereas testosterone UDP-glucuronosyltransferase was eluted at around pH 8.5, with a subunit Mr of 50 000.
| S-EPMC1146536 | biostudies-other
Project description:Oestradiol benzoate, testosterone propionate, progesterone, corticosterone, 3-methylcholanthrene and phenobarbital were administered to Wistar rats at the pubertal period, and their effects on hepatic UDP-glucuronosyltransferase activities were determined. Pretreatment with oestradiol benzoate had a temporary suppressive effect on androsterone UDP-glucuronosyltransferase activity in rats with the high-activity phenotype of androsterone glucuronidation. The effect was marked in 40-day-old rats, but was not found in older rats. Androsterone UDP-glucuronosyltransferase activity was induced by phenobarbital in rats with the high-activity phenotype, but not in rats with the low-activity phenotype. Foster-feeding experiments showed that breast milk did not alter the genetically determined expression of androsterone UDP-glucuronosyltransferase activity in Wistar rats. In contrast, 4-nitrophenol UDP-glucuronosyltransferase activity was not affected by steroid hormones, but was highly induced by 3-methylcholanthrene.
| S-EPMC1144182 | biostudies-other
Project description:The mechanism of shengmai injection- (SMI-) related drug-drug interaction remains unclear. Evaluation of the inhibition potential of SMI's ingredients towards UDP-glucuronosyltransferases (UGTs) activity will provide a new insight to understand SMI-related drug-drug interaction. In vitro incubation system to model UGT reaction was used. Recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reactions were employed to phenotype the inhibition profile of maidong's components towards the activity of UGT isoforms. Different inhibition potential of maidong's components towards various UGT isoforms was observed. Based on the inhibition kinetic investigation results, ophiopogonin D (OD) noncompetitively inhibited UGT1A6 and competitively inhibited UGT1A8, ophiopogonin D' (OD') noncompetitively inhibited UGT1A6 and UGT1A10, and ruscorectal (RU) exhibited competitive inhibition towards UGT1A4. The inhibition kinetic parameters were calculated to be 20.6, 40.1, 5.3, 9.0, and 0.02 μM, respectively. In combination with our previous results obtained for the inhibition of UGT isoforms by ginsenosides and wuweizi components, the important SMI ingredients exhibiting strong inhibition towards UGT isoforms were highlighted. All the results obtained in the present study provide a new insight to understand SMI-related drug-drug interaction.
| S-EPMC4229968 | biostudies-literature
Project description:We propose the existence in rat liver endoplasmic reticulum (ER) of two asymmetric carrier systems. One system couples UDP-N-acetylglucosamine (UDPGlcNAc) transport to UDP-glucuronic acid (UDPGlcA) transport. When UDPGlcNAc was presented at the cytosolic side of the ER, it then acted as a weak inhibitor of UDPGlcA uptake. By contrast, UDPGlcNAc produced a forceful trans-stimulation of microsomal UDPGlcA uptake when it was present within the lumen of the ER. Likewise, cytosolic UDPGlcA strongly trans-stimulated efflux of intravesicular UDPGlcNAc, whereas cytosolic UDPGlcNAc was ineffective in trans-stimulating efflux of UDPGlcA. A second asymmetric carrier system couples UDPGlcNAc transport to UMP transport. Microsomal UDPGlcNAc influx was markedly stimulated by UMP present inside the microsomes. Such stimulation was only apparent when microsomes had been preincubated and thereby preloaded with UMP, indicating that UMP exerted its effect on UDPGlcNAc uptake by trans-stimulation from the lumenal side of the ER membrane. Contrariwise, extravesicular UMP only minimally trans-stimulated efflux of intramicrosomal UDPGlcNAc. It is widely accepted that UDPGlcNAc acts as a physiological activator of hepatic glucuronidation, but the mechanism of this effect has remained elusive. Based on our findings, we propose a model in which the interaction of two asymmetric transport pathways, i.e. UDPGlcA influx coupled to UDPGlcNAc efflux and UDPGlcNAc influx coupled to UMP efflux, combined with intravesicular metabolism of UDPGlcA, forms a mechanism that leads to stimulation of glucuronidation by UDPGlcNAc.
| S-EPMC1136466 | biostudies-other
Project description:Male Donryu, Wistar King rats showed discontinuous variations in hepatic microsomal UDP-glucuronyltransferase activities towards androsterone, but not towards testosterone, bilirubin, phenolphthalein and 4-nitrophenol. Fresh microsomal fraction with a low transferase activity towards androsterone formed 0.049--0.080 nmole of glucuronide/min per mg of protein, whereas fresh microsomal fraction with a high transferase activity towards androsterone formed 0.335--0.557 nmol of glucuronide/min per mg of protein. The microsomal fraction with low enzyme activity towards androsterone was not stimulated by treatment with Triton X-100 or freezing and thawing. In contrast, male Long Evans and Sprague-Dawley rats did not exhibit such diversity.
| S-EPMC1186654 | biostudies-other
Project description:The UDP-glucuronosyltransferase (UGT) system fulfils a pivotal role in the biotransformation of potentially toxic endogenous and exogenous compounds. Here we report that the activity of UGT in rat liver is stimulated by UDP-xylose. This stimulation was found in native microsomal vesicles as well as in the intact endoplasmic reticulum (ER) membrane, as studied in permeabilized hepatocytes, indicating the potential physiological importance of UDP-xylose in the regulation of UGT. We present evidence that UDP-xylose enhances UGT activity by stimulation of (i) the uptake of UDP-glucuronic acid across the ER membrane and (ii) the elimination of the UDP and/or UMP reaction product out of the ER lumen. UDP-xyloe produced a marked trans-stimulation of microsomal UDP-glucuronic acid uptake when it was present within the lumen of the ER. When UDP-xylose was presented at the cytosolic side of the ER, it acted as a weak inhibitor of UDP-glucuronic acid uptake. Likewise, cytosolic UDP-glucuronic acid strongly trans-stimulated efflux of intravesicular UDP-xylose, whereas cytosolic UDP-xylose was inefficient in trans-stimulating efflux of UDP-glucuronic acid. Microsomal UDP-xylose influx was markedly stimulated by UMP and UDP. Such stimulation was only apparent when microsomes had been preincubated and thereby preloaded with UMP or UDP, indicating that UMP and UDP exeted their effect on UDP-xylose uptake by trans-stimulation from the luminal side of the ER membrane.
| S-EPMC1217170 | biostudies-other
Project description:A cDNA clone (HLUG 25) encoding the complete sequence of a human liver UDP-glucuronosyltransferase was isolated from a lambda gt11 human liver cDNA library. The library was screened by hybridization to a partial-length human UDP-glucuronosyltransferase cDNA (pHUDPGT1) identified from a human liver pEX cDNA expression library by using anti-UDP-glucuronosyltransferase antibodies. The authenticity of the cDNA clone was confirmed by hybrid-select translation and extensive sequence homology to rat liver UDP-glucuronosyltransferase cDNAs. The sequence of HLUG 25 cDNA was determined to be 2104 base-pairs long, including a poly(A) tail, and contains a long open reading frame. The possible site of translation initiation of this sequence is discussed with reference to a rat UDP-glucuronosyltransferase cDNA clone (RLUG 38).
| S-EPMC1147744 | biostudies-other
Project description:ObjectivesCarbamazepine (CBZ), an anti-seizure drug, is widely prescribed for the management of focal seizures. At a given therapeutic dose, CBZ exhibits marked interindividual variation in the plasma CBZ levels. The aim wasto study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on plasma carbamazepine (CBZ) levels in persons with epilepsy (PWE) from South India.Methods115 PWE belong to South India origin who are on carbamazepine monotherapy were recruited. Genotyping of the two variants weredone using RT-PCR method. PWE who had seizure freedom for one year and their last dose which was not changed for one year duration were included and their plasma levels of CBZ and its active metabolite CBZ 10,11 epoxide were analysed by reverse phase HPLC.ResultsIn EPHX1 c. 337 (T>C) polymorphism, the PWE carrying CC had lower plasma CBZ levels when compared to CT genotype (2.45 μg/ml vs 3.15 μg/ml. In UGT2B7*2, PWE carrying homozygous mutant TT had higher levels when compared with CT (3.09 μg/ml vs 2.74 μg/ml) genotype but found no statistical significance. Mutant genotype of EPHX1 (CC) had higher metabolic ratio compared to TT genotype (1.33 vs 1.17) but not found to be statistically significant. Mutant genotype of UGT2B7*2 (TT) was found to be having lower metabolic ratio when compared with CC genotype (1.18 vs 1.35; p value =0.08).ConclusionPWE carrying EPHX1 c.337 T>C (rs1051740) and UGT2B7*2 (rs7439366) genetic polymorphisms did not affect the plasma CBZ levels and metabolic ratio of PWE of South Indian origin. However, this finding should be confirmed in a larger sample size which may help in optimization and personalized CBZ therapy in South Indians.
| S-EPMC10501538 | biostudies-literature
Project description:Qualitative and quantitative differences of purified hepatic 3 alpha-hydroxysteroid UDP-glucuronosyltransferase were investigated in Wistar and Sprague-Dawley rats. Individual differences in the glucuronidation rate of androsterone and chenodeoxycholic acid were observed in hepatic microsomal fractions from Wistar but not Sprague-Dawley rats. No individual variation was observed in the glucuronidation of testosterone, p-nitrophenol or oestrone. The 3 alpha-hydroxysteroid UDP-glucuronosyltransferases from livers of Wistar and Sprague-Dawley rats were isolated and highly purified by using Chromatofocusing and affinity chromatography. The amount of 3 alpha-hydroxysteroid UDP-glucuronosyltransferase in the liver of Wistar rats exhibiting low rates for androsterone glucuronidation is about 10% or less than that found in hepatic microsomal fractions obtained from Wistar rats having high rates for androsterone glucuronidation. The apparent Km for androsterone with purified 3 alpha-hydroxysteroid UDP-glucuronosyltransferase from Wistar rats with high glucuronidation activity (6 microM) was not different from that observed for the enzyme purified from Sprague-Dawley animals, whereas that for the enzyme purified from Wistar rats with low glucuronidation activity was substantially higher (120 microM). Despite the differences in apparent Km values for androsterone, the apparent Km for UDP-glucuronic acid (0.3 mM) was not different in the different populations of rats.
| S-EPMC1152631 | biostudies-other