Inhibition of UDP-glucuronosyltransferases in rat liver microsomes by natural mutagens and carcinogens

Abstract

Eight toxic compounds of natural origin present in the human diet or used as drugs were tested as inhibitors of UDP-glucuronosyltransferase (UGT) activity in rat liver microsomes with 1-naphthol (1-NA), phenolphthalein (PPh) and 4-nitrophenol (4-NP) as substrates. Strong inhibitory effects were observed with tannic acid (tannin) and the antifungal drug griseofulvin (GF): at a concentration of 1 mM, the two compounds completely suppressed the glucuronidation of 1-NA and PPh, respectively. A concentration of 0.1 mM still proved to be highly inhibitory, and even at a concentration as low as 50 microM, tannin produced nearly 50% inhibition of 1-NA conjugation. The UGT isoforms converting 4-NP were less sensitive to the tested compounds (with the exception of GF). Kinetic studies with tannin revealed an uncompetitive type of inhibition toward 1-NA, with an apparent Ki value of 20 microM. The inhibition by GF was non-competitive with respect to PPh and was of a mixed type toward UDP-glucuronic acid, with apparent Ki values of 40 microM and 30 microM, respectively. Tannin and GF did not act as substrates for rat microsomal UGT.

Effects of Dietary Components on Testosterone Metabolism via UDP-Glucuronosyltransferase

“…Early studies reported the effects of drugs and dietary compounds on UGT activity in isolated microsomes or in rats without detailing the specific UGT isozymes involved (9, 10). Liver microsomal glucuronidation of estradiol and estrone was inhibited by green and black teas, along with a constituent catechin [(-)-epigallocatechin gallate] and several flavonoids (kaempferol, quercetin, rutin, flavone, naringenin, hesperetin) (11).…”

Au@pNIPAM Colloids as Molecular Traps for Surface‐Enhanced, Spectroscopic, Ultra‐Sensitive Analysis

“…Apart from the SERS enhancement, this system can also be used to modulate the fluorescence intensity of adsorbed chromophores as a function of temperature. [13] The synthesis of the core-shell Au@pNIPAM colloids has been described in detail elsewhere [7] and involves initial growth of a thin polystyrene (PS) shell on cetyl trimethyl ammonium bromide (CTAB) coated, 67 nm gold nanoparticles, followed by polymerization of N-isopropylacrylamide (NIPAM) and a cross-linker (N,N-methylenebisacrylamide; see Experimental Section for details). Through a rational choice of model analytes, we demonstrate the application of these thermoresponsive hybrid materials for surface-enhanced Raman scattering, fluorescence, and resonance Raman scattering (SERS, SEF, and SERRS, respectively).…”

Expression of UDP-glucuronosyltransferase 1A6 isoform in Caco-2 cells stimulated with lipopolysaccharide

“…The endogenous bile acids (cholic acid, chenodeoxycholic acid, and deoxycholic acid) have been reported to inhibit bilirubin glucuronidation in digitonin-disrupted rat liver microsomes. 24 Impairment of the glucuronidation reaction by clinically used drugs is an important aspect of UGT inhibition studies. It was reported that some drugs are able to interfere with the glucuronidation of endogenous component, therapeutic agents, and xenobiotics.…”