Effect of Chronic Renal Insufficiency on Hepatic and Renal Udp-Glucuronyltransferases in Rats

Abstract

ABSTRACT:Significant evidence exists regarding altered CYP450 enzymes in chronic renal insufficiency (CRI), although none exists for the phase II enzymes. The objective of this study was to investigate the effect of CRI on hepatic and renal UDP-glucuronyltransferase (UGT) enzymes. Three groups of rats were included: CRI induced by the 5/6th nephrectomy model, control, and control pair-fed (CPF) rats. UGT activities were determined in liver and kidney microsomes by the 3-and 17-glucuronidation of ␤-estradiol (E2-3G and E2-17G), glucuronidation of 4-methylumbelliferone (4-MUG), and 3-glucuronidation of morphine (M3G). UGT isoforms responsible for these catalytic activities were screened using recombinant rat UGT1A1, UGT1A2, UGT1A3, UGT1A7, UGT2B2, UGT2B3, and UGT2B8. UGT protein levels were examined by Western blot analysis using polyclonal antibodies. There was no significant difference between CRI and CPF rats in hepatic and/or renal E2-3G (UGT1A1), E2-17G (UGT2B3), 4-MUG (UGT1A6), and M3G (UGT2B1) formation. Formation of E2-17G and 4-MUG in the liver and E2-3G and 4-MUG in the kidney was significantly reduced (p < 0.05) in CPF and CRI rats compared with control rats. The down-regulated glucuronidation activities were accompanied by corresponding reductions in protein content of specific UGT isoforms. These results suggest that CRI does not seem to influence the protein levels or catalytic activity of most of the major hepatic or renal UGT enzymes. The observed down-regulation of hepatic and renal UGTs in CRI and CPF rats could be caused by restricted food intake in these groups of rats.

Analysis and evaluation of pyrethroid exposure in human population based on biological monitoring of urinary pyrethroid metabolites

“…25) Thus, it is reasonable to suppose that the 3-PBA excretion rate might change depending on population-and gender-related differences in the expression and activity of the carboxylesterase, ADH, ALDH, CYP and UDP-glucuronosyltransferase isozymes in the liver and other organs, as suggested from experimental studies. [26][27][28][29][30][31][32][33] So far, there are few human data on the toxicokinetics of PYRs. When cypermethrin was administered orally to male human volunteers as a single dose of 8 mmol, about 1.6 mmol 3-PBA and 4.3 mmol DCCA (sum of free and glucuronide forms) were excreted in urine by 120 h after administration.…”

Species and Tissue Differences in β-Estradiol 17-Glucuronidation

“…15) Ugt2b2 and Ugt2b3 have been reported to be highly expressed in the liver, 16) suggesting that these isoforms may be associated with E17G formation in rat liver. Ugt1a2 mRNA was not expressed in the liver or kidney but was found predominantly in the small intestine.…”

“…14) UGT1A4 and UGT2B7 mRNAs are expressed at high levels among the hepatic UGT isoforms involved in E17G formation, whereas UGT1A10 has been found predominantly in the extrahepatic tissues. 2) In rats, E17G is formed by Ugt1a2, Ugt2b2, and Ugt2b3 15) and there is a tissue difference in the mRNA expression of these Ugt isoforms.…”

Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases

“…Remarkable decreases in the functional expression of drug-metabolizing enzymes that mediate nonrenal drug clearance, particularly phase I oxidation by cytochrome P450 (P450) enzymes, have been well documented in the setting of kidney disease (Naud et al, 2012;Lalande et al, 2014;Yeung et al, 2014). Phase II conjugation via acetylation (Simard et al, 2008) is also decreased by kidney disease, but glucuronidation is not affected (Yu et al, 2006). However, the effect of CKD on other drug-metabolism pathways is less clear.…”