Significance Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a broad-spectrum antimicrobial agent that has become one of the most common additives used in consumer products. As result, TCS significantly affected environment and been frequently detected human body fluids. Through long-term feeding study, we found enhances hepatocyte proliferation, fibrogenesis, oxidative stress, which, believe, can be driving force for developing advanced liver disease mice. Indeed, strongly...

Through a multiplex promoter spanning 218 kb, the phase II UDP-glucuronosyltransferase 1A ( UGT1 ) gene encodes at least eight differently regulated mRNAs whose protein products function as principal means to eliminate vast array of steroids, heme metabolites, environmental toxins, and drugs. The orphan nuclear receptors pregnane X receptor (PXR) constitutive androstane (CAR) were originally identified sensors able respond numerous environmentally derived foreign compounds (xenobiotics)...

Kinetic and inhibitor studies using cDNA-expressed enzymes human liver microsomes have characterized the specificity of a range cytochrome P450 (CYP) 1A substrate probes towards two isoforms comprising this subfamily. Expressed CYP1A1 CYP1A2 both catalyzed O-deethylation phenacetin, although apparent Km was about 4-fold lower for (25 vs. 108 microM). Phenacetin exhibited biphasic kinetics in microsomes, high-affinity component (9 +/- 6 microM) consistent with involvement reaction. The...

UDP-glucuronosyltransferases (UGT) catalyze the conjugation of lipophilic exobiotic and endobiotic compounds, which leads to excretion hydrophilic glucuronides via bile or urine. By a mechanism exon sharing, transcripts individual first cassettes located at 5' end human UGT1A locus are spliced exons 2-5, leading expression least nine UGT genes. Recently, tissue-specific has been demonstrated in extrahepatic tissue, identification UGT1A7 UGT1A10 mRNA (Strassburg, C. P., Oldhafer, K., Manns,...

Family 1 UDP-glucuronosyltransferases (UGTs) (UGT1A) are encoded by a locus that predicts the existence of at least nine individual proteins. The different proteins generated exon-sharing, which results in production family contain identical, 245-amino acid, carboxyl-terminal domains and an amino-terminal region approximately 280 amino acids. diversity the<i>UGT1A</i> suggests complex regulation, most likely designed to account for variable specific glucuronidation requirements. However,...

UDP-glucuronosyltransferases (UGTs) convert dietary constituents, drugs, and environmental mutagens to inactive hydrophilic glucuronides. Recent studies have shown that the expression of <i>UGT1</i> <i>UGT2</i> gene families is regulated in a tissue-specific fashion. Human small intestine represents major site resorption constituents orally administered drugs plays an important role extrahepatic UGT directed metabolism. Expression 13 <i>UGT1A</i> <i>UGT2B</i>genes coupled with functional...

The gene for cytochrome P4501A2 is constitutively expressed in the liver of vertebrates and shows induced expression when an organism exposed to polycyclic aromatic hydrocarbons halogenated hydrocarbons. To identifyDNAelements regulating transcription human CYPlA2 gene, transient transfection experiments were conducted hepatoma cell line HepG2.Dissection S'-flanking portion C Y P l A 2 identified two regions that contributed overall induction by 3-methylcholanthrene.One region located at...

Mouse liver cytochromes P1-450 and P3-450 represent those forms of polycylic hydrocarbon-induced P-450 most closely associated with induced aryl hydrocarbon (benzo[a] pyrene) hydroxylase acetanilide 4-hydroxylase activity, respectively. These two proteins are controlled by the Ah receptor: C57BL/6N mice possess high-affinity receptor; DBA/2N mice, poor-affinity receptor. 3-Methylcholanthrene at highest dose technically possible induces both in but not whereas sufficiently high doses...

The formation of β-d-glucopyranosides (glucuronides) by the UDP-glucuronosyltransferases (UGTs) is a significant metabolic pathway that facilitates elimination small hydrophobic molecules such as drugs, dietary constituents, steroids, and bile acids. We elucidate here an anti-oxidative response leads to induction UGT1A1 through Nrf2-Keap1 pathway. When human HepG2 cells were treated with prooxidants tert-butylhydroquinone β-naphthoflavone, cellular glucuronidation activities increased....

Significance Camptothecin (CPT)-11 (irinotecan) is an antitumor agent used in cancer chemotherapy primarily for the treatment of solid tumors. CPT-11 a prodrug that metabolized by carboxylesterases to DNA topoisomerase 1 inhibitor, called SN-38. Detoxification SN-38 occurs UDP-glucuronosyltransferase 1A1 (UGT1A1)-dependent glucuronidation. A serious side effect SN-38–induced intestinal toxicity, which believed result part from delivery into tissue through enterohepatic circulation. By...

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an important physiological role by contributing to the metabolism of endogenous substances such as bilirubin in addition xenobiotics and drugs. The UGT1A1 gene has been shown be inducible nuclear receptors steroid xenobiotic receptor (SXR) constitutive active receptor, CAR. In this report, we show that human hepatoma HepG2 cells is also with aryl hydrocarbon (Ah receptor) ligands 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD), β-naphthoflavone,...

Mycophenolic acid (MPA) is primarily metabolized to a phenolic glucuronide (MPAG) as well two further minor metabolites: an acyl (AcMPAG) and glucoside (MPAG1s). This study presents investigations of the formation these metabolites by human liver (HLM), kidney (HKM), intestinal (HIM) microsomes, recombinant UDP‐glucuronosyltransferases. HLM ( n =5), HKM =6), HIM =5) UGTs were incubated in presence either UDP‐glucuronic or UDP‐glucose various concentrations MPA. Metabolite was followed...

Transcriptional activation of the human CYP1A1 gene by halogenated and polycyclic aromatic hydrocarbons is mediated aryl hydrocarbon receptor (AhR) complex, a ligand-dependent transcription factor. A competent AhR comprises at least two components following nuclear translocation DNA binding, translocator (Arnt) protein, whose combined action on shown to be dependent upon functional protein kinase C (PKC). In present study, we examined effects phorbol 12-myristate 13-acetate, potent PKC...

Human UDP-glucuronosyltransferases (UGTs) are expressed in a tissue-specific fashion hepatic and extrahepatic tissues [Strassburg, Manns Tukey (1998) J. Biol. Chem. 273, 8719-8726]. Previous work suggests that these enzymes play protective role chemical carcinogenesis (1997) Cancer Res. 57, 2979-2985]. In this study, UGT1 UGT2 gene expression was investigated human oesophageal epithelium squamous-cell carcinoma addition to the characterization of individual UGT isoforms using recombinant...

Interindividual variation in the spontaneous and glucocorticoid-or rifampicin-inducible expression of CYP3A cytochromes P450, dominant froms this supergene family that catalyze oxidation numerous drugs environmental chemicals human liver, remains largely unexplained, due part to lack a validated animal model. We analyzed 5'-flanking sequences genes from rat (CYP3A23, CYP3A2), rabbit (CYP3A6), (CYP3A4, CYP3A5, CYP3A7) found variable regions separated by three areas (consensus I, II, III)...

In the presence of halogenated and polycyclic aromatic hydrocarbons, CYP1A1 gene is regulated through induction after ligand binding to cytosolic Ah receptor (AhR). Ligand-dependent AhR activation leads nuclear translocation dioxin-responsive element (DRE) sequences, an event that initiates transcriptional gene. We recently established a human hepatoma cell line stably integrated with promoter 5'-flanking enhancer sequences fused firefly luciferase This line, 101L, was used determine whether...