Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Triclocarban (3,4,4′-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car−/− mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human health effects from exposure to TCC

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities

Developmental regulation of flavin-containing monooxygenase (FMO) form 1 and form 2 mRNA in fetal and neonatal rabbit

The mammalian FMO represents a multigene family which oxygenates a large number of xenobiotics. No physiological role has been determined for FMO, although synthesis of disulfide bonds and detoxification of dietary chemicals have been suggested. Five FMO gene subfamilies, each containing a single gene, have been identified. In this study, we determined the patterns of fetal and neonatal development of FMO1 and FMO2 in rabbit liver and lung. The expression of two major isoforms, FMO1 and FMO2, in fetal and neonatal animals were characterized at the steady state levels of mRNA. Northern and slot blot analyses were performed with cDNA probes for each isoform to provide a qualitative and quantitative profile. In order to relate developmental changes in FMO to the metabolism of xenobiotics for which lung is a target organ, the developmental expression of lung FMO (FMO2) mRNA is compared to rabbit CYP2B4 and CYP4B1 which are the major constitutive P450s in lung. The results show that the expression of FMO1 and FMO2 is tissue-dependent, although the mechanisms controlling the mRNA expression, such as rate of transcription, processing of primary RNA, efficiencies of nucleocytoplasmic transport and stability of RNA in the cytoplasm, are still unknown. The results indicate that the early development- and tissue-specific expression patterns of mRNA for FMO1 and FMO2 might play a significant role in the target organ toxicity of xenobiotics in the rabbit fetus and neonate

Identification and characterization of flavin-containing monooxygenase isoform 2 (FMO2) in Rhesus monkey and examination of a human FMO2 polymorphism

Flavin-containing monooxygenase (FMO, EC1.14.13.8) comprises a family of xenobiotic-metabolizing enzymes that catalyze the oxygenation of a wide variety of xenobiotics, most commonly nitrogen and sulfur. Mammals express five different FMOs in a species- and tissue- specific manner. FMO2, is expressed predominantly in lung and differs from other FMOs in that it can catalyze the N-oxygenation of certain primary alkylamines. From its initial discovery as an unique form of FMO in lung, FMO2 has been studied primarily using a rabbit animal model. The initial goal of this research was to characterize this protein in a primate animal model. To understand FMO2 protein structure at the molecular level, we first cloned cDNA from a monkey lung cDNA library. Monkey FMO2 is expressed predominantly in lung. The high expression levels and broad substrate specificity in monkey, suggests that FMO2 plays a role in xenobiotic metabolism in this primate model. We then established a heterologous expression system to generate FMO2 with biological functionality in vitro. FMO2 from baculovirus-mediated expression resembled monkey and rabbit microsomal FMO2 immunochemically and catalytically. The successful FMO2 expression in the baculovirus system will serve as a valid tool for structure studies of protein functional domains, as well as, the amino acids responsible for enzyme properties of chimeras. Human FMO2 encodes a truncated protein containing 471 amino acid residues, 64 amino acids shorter in its C-terminal than orthologs in other species. We characterized human FMO2 in terms of gene polymorphism (genotyped by Dr. Hines), protein levels and catalytic activity with human lung microsomes. An ethnically related polymorphism was observed, in which all Caucasians genotyped to date are homozygous for a truncated, enzymatically inactive enzyme which may not even be translated. Approximately 15% of humans of African descent are heterozygous for full-length FMO2, but the level of expression may not be sufficient to significantly effect drug metabolism in the lung. The results of truncated FMO2 produced from baculovirus expression suggest that the C-terminal of FMO2 might be responsible for enzyme stability and/or proper structure necessary to exert fully enzyme activity. We conclude that the human FMO2 possesses unique features compared to all other mammals examined to date including other primates

Triclosan: A Widespread Environmental Toxicant with Many Biological Effects

Triclosan (TCS) is a broad-spectrum antimicrobial agent that has been added to personal care products, including hand soaps and cosmetics, and impregnated in numerous different materials ranging from athletic clothing to food packaging. The constant disposal of TCS into the sewage system is creating a major environmental and public health hazard. Owing to its chemical properties of bioaccumulation and resistance to degradation, TCS is widely detected in various environmental compartments in concentrations ranging from nanograms to micrograms per liter. Epidemiology studies indicate that significant levels of TCS are detected in body fluids in all human age groups. We document here the emerging evidence--from in vitro and in vivo animal studies and environmental toxicology studies--demonstrating that TCS exerts adverse effects on different biological systems through various modes of action. Considering the fact that humans are simultaneously exposed to TCS and many TCS-like chemicals, we speculate that TCS-induced adverse effects may be relevant to human health

volume bioassays to assess CYP3A4-mediated drug interactions: induction and inhibition in a single cell line. Drug Metab Dispos

ABSTRACT: Exposure to certain xenochemicals can alter the catalytic activity of the major drug-metabolizing enzyme, CYP3A4, either by enhancing expression of this cytochrome P450 or inhibiting its activity. Such alterations can result in adverse consequences stemming from drug-drug interactions. A simplified and reliable tool for detecting the ability of candidate drugs to alter CYP3A4 levels or inhibit catalytic activity was developed by stable integration of human pregnane X receptor and a luciferase vector harboring the CYP3A4 enhancers. Treatment of stable transformants, namely DPX-2, with various concentrations of inducers including rifampicin, mifepristone, troglitazone, methoxychlor, and kava produced dose-dependent increases in luciferase expression (between 2-and 40-fold above dimethyl sulfoxide-treated cells). Northern blot analyses of CYP3A4 mRNA in DPX-2 cells exhibited a good correlation to results generated with the reporter gene assay (r 2 ‫؍‬ 0.5, Drug interactions frequently occur when one drug modulates the metabolism of a second drug by inhibition or induction of a specific P450 enzyme. Given that CYP3A4 is the most abundant hepatic P450 enzyme and is responsible for the metabolism of a large number of currently used therapeutic agents, a major focus in determining the causes of drug interactions centers around identification of xenochemicals that alter the expression of CYP3A4 CYP3A4 induction is frequently considered clinically less important than inhibition of its catalytic activity because induction is expected to reduce the efficacy, rather than cause toxicity, of coadministered CYP3A substrates. However, CYP3A4 inducers such as rifampicin and rifabutin can reduce plasma concentrations of certain drugs up to 40-fold, effectively abolishing their efficacy Article, publication date, and citation information can be found a