In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Human UDP-Glucuronosyltransferases: Metabolism, Expression, and Disease

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

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Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies

The changing faces of glutathione, a cellular protagonist

[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([

Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.

Numerous studies have investigated the environmental occurrence, human exposure, and toxicity of bisphenol A (BPA). Following stringent regulations on the production and usage of BPA, several bisphenol analogues have been produced as a replacement for BPA in various applications. The present review outlines the current state of knowledge on the occurrence of bisphenol analogues (other than BPA) in the environment, consumer products and foodstuffs, human exposure and biomonitoring, and toxicity. Whereas BPA was still the major bisphenol analogue found in most environmental monitoring studies, BPF and BPS were also frequently detected. Elevated concentrations of BPAF, BPF, and BPS (i.e., similar to or greater than that of BPA) have been reported in the abiotic environment and human urine from some regions. Many analogues exhibit endocrine disrupting effects, cytotoxicity, genotoxicity, reproductive toxicity, dioxin-like effects, and neurotoxicity in laboratory studies. BPAF, BPB, BPF, and BPS have been show...

Bisphenol Analogues Other Than BPA: Environmental Occurrence, Human Exposure, and Toxicity-A Review.

1. The activities of the ethoxycoumarin O-deethylase (ECOD), epoxide hydrolase (EH), UDP-glucuronyl transferase (GT), glutathione S-transferase (GST), acetyl transferase (AT) and sulphotransferase (ST) were measured in 6 liver, 8 lung, 8 kidney, 8 intestinal mucosa and 22 urinary bladder mucosa specimens from human subjects. EH and GT were studied with styrene oxide and 1-naphthol, respectively, as substrates, GST, AT and ST were studied with benzo(a)pyrene-4,5-oxide, p-aminobenzoic acid and 2-naphthol, respectively. 2. The enzyme activities were detectable at significant rates in liver, lungs, kidneys and gut. In urinary bladder, EH, GT, GST and ST only were detectable. The liver catalyzed the various reactions at higher rates than did other tissues. 3. Of the extrahepatic tissues, the intestinal mucosa contained the highest activities of AT (50% of liver) and ST (30% of liver), whereas kidneys contained the highest activity of GT (50% of liver) and GST (80% of liver). GST was the enzyme with the widest tissue distribution.

Tissue distribution of drug-metabolizing enzymes in humans.

1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. It has been shown that the compound is sulphated in human liver and the aims of the present investigation were to study resveratrol glucuronidation in human liver microsomes and to determine whether flavonoids inhibit resveratrol glucuronidation. 2. A simple and reproducible radiometric assay for resveratrol glucuronidation was developed. The assay employed uridine-5'-diphosphoglucuronic acid-[14C] and unlabelled resveratrol. Resveratrol-glucuronide was isolated by TLC. The intra- and interassays variabilities were 1 and 1.5%, respectively. 3. The rate of resveratrol glucuronidation was measured in 10 liver samples. The mean +/- SD and median of resveratrol glucuronidation rate were 0.69 +/- 0.34 and 0.80 nmol/min/mg, respectively. Resveratrol glucuronosyl transferase followed Michaelis-Menten kinetics and the Km and Vmax (mean +/- SD; n = 5) were 0.15 +/- 0.09 mM and 1.3 +/- 0.3 nmol/min/mg, respectively. The intrinsic clearance was 11 +/- 4 x 10(-3) ml/min.mg. 4. The flavonoid quercetin inhibited resveratrol glucuronidation and its IC50 (mean +/- SD; n = 3) was 10 +/- 1 microM. Myricetin, catechin, kaempferol, fisetin and apigenin (all at 20 microM) inhibited resveratrol glucuronidation and the percent of control ranged between 46% (catechin) to 72% (apigenin). 5. The present results show that resveratrol is glucuronated in the human liver. Glucuronidation may reduce the bioavailability of this compound however, flavonoids inhibit resveratrol glucuronidation and such an inhibition might improve the bioavailability of resveratrol.

Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver.

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.

Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5'-diphosphoglucuronic acid in human tissues.

1. The rate of conjugation of benzoic acid with glycine was measured in the homogenates of 110 specimens of human liver and in 67 specimens of human renal cortex.2. The assay for the formation of benzoyl glycine consisted of measuring the formation of benzoyl glycine from (14C) benzoic acid and glycine in the presence of coenzyme A and ATP.3. In human liver, the mean (± SD) and coefficient of variation for the formation rate of benzoyl glycine were 254±90.5 nmol min-1 per g liver and 36%, respectively. There was a weak, but significant, negative correlation (r = -0.339, p < 0.001) between the rate of formation of benzoyl glycine and the liver donor's age.4. In the human kidney, the rate of benzoyl glycine formation was normally distributed. The mean (± SD) and coefficient of variation were 321 ± 99.3 nmol min-1 per g kidney and 31%, respectively.5. These in vitro results are consistent with the view that the in vivo rate of conjugation of carboxylic acid with glycine varies among subjects and is normally ...

Conjugation of benzoic acid with glycine in human liver and kidney: A study on the interindividual variability

1. Glutathione transferase and epoxide hydratase activities were determined in liver, lung and kidney of nine species including man with [7-3H]styrene oxide as substrate. 2. Activity was detectable in all tissues. The activities of both enzymes were higher in the liver of all species than in either kidney or lung. 3. The baboon had the highest hepatic epoxide hydratase activity, 31 \pm 2nmol/mg per min, while the mouse had the lowest hepatic activity, 1.9 \pm 0.1 nmol/mg per min. 4. Rodent species had higher glutathione transferase activity than non-rodent species, mouse liver having the highest activity, 143\pm13nmol conjugate/mg per min. 5. Taking all the data into account, it is concluded that no single species of those studied is a suitable model for the disposition of epoxides in man.

G. M. Pacifici

Papers

Tissue distribution of drug-metabolizing enzymes in humans.

Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver.

Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 5'-diphosphoglucuronic acid in human tissues.

Conjugation of benzoic acid with glycine in human liver and kidney: A study on the interindividual variability

Tissue and species differences in enzymes of epoxide metabolism