Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.

Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1ΔHep) and the intestine (Ugt1ΔGI). Control (Ugt1F/F), Ugt1ΔHep, and Ugt1ΔGI adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11–treated Ugt1ΔHep mice showed a similar lethality rate to the CPT-11–treated Ugt1F/F mice. However, Ugt1ΔGI mice were highly susceptible to CPT-11–induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.

High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9-UGT1A genes including UGT1A1, was expressed in Ugt1−/− mice. Because the most common clinical condition associated with jaundice in adults is Gilbert’s syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert’s UGT1A1*28 allele [Tg(UGT1A1*28)Ugt1−/− mice] or the normal UGT1A1*1 allele [Tg(UGT1A1*1)Ugt1−/− mice]. Adult Tg(UGT1A1*28)Ugt1−/− mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1A1*1)Ugt1−/− mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert’s UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In ∼10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice.

Background & AimsThe UDP-glucuronosyltransferases (UGTs) are a part of the cell machinery that protects the tissues from a toxicant insult by environmental and host cell metabolites. We investigated the mechanism behind tumor growth and UGT repression.MethodsWe initially silenced the Ugt1 locus in human colon cell lines and investigated markers and responses linked to p53 activation. To examine the role of the Ugt1 locus in p53-directed apoptosis and tumorigenesis, experiments were conducted to induce acute colon inflammation and chemically induced colon cancer in mice where we have selectively deleted the Ugt1 locus in the intestinal epithelial cells (Ugt1ΔIEC mice).ResultsKnockdown of the UGT1A proteins by RNAi in human colon cancer cells and knockout of the Ugt1 locus in intestinal crypt stem cells reduces phosphorylated p53 activation and compromises the ability of p53 to control apoptosis. Targeted deletion of intestinal Ugt1 expression in Ugt1ΔIEC mice represses colon inflammation-induced p53 production and proapoptotic protein activation. When we induced colon cancer, the size and number of the tumors were significantly greater in the Ugt1ΔIEC mice when compared with wild-type mice. Furthermore, analysis of endoplasmic reticulum (ER) stress-related markers indicated that lack of UGT1A expression causes higher ER stress in intestinal epithelial cells and tissue, which may account for the lower expression of p53.ConclusionsOur results demonstrate that UGT1A expression is required to maintain and sustain p53 activation in stress-induced colon epithelial cells and has a significant impact on p53-mediated apoptosis and tumor suppression, thus protecting the colon tissue from neoplastic transformation.

•Breast-feeding can be a factor for the development of neonatal hyperbilirubinemia.•UDP-glucuronosyltransferase (UGT) 1A1 is the sole bilirubin-metabolizing enzyme.•Extrahepatic UGT1A1 plays an important role in bilirubin metabolism.•We discuss the potential mechanism of breast milk-induced neonatal jaundice.Newborns commonly develop physiological hyperbilirubinemia (also known as jaundice). With increased bilirubin levels being observed in breast-fed infants, breast-feeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia. Bilirubin undergoes selective metabolism by UDP-glucuronosyltransferase (UGT) 1A1 and becomes a water soluble glucuronide. Although several factors such as gestational age, dehydration and weight loss, and increased enterohepatic circulation have been associated with breast milk-induced jaundice (BMJ), deficiency in UGT1A1 expression is a known cause of BMJ. It is currently believed that unconjugated bilirubin is metabolized mainly in the liver. However, recent findings support the concept that extrahepatic tissues, such as small intestine and skin, contribute to bilirubin glucuronidation during the neonatal period. We will review the recent advances made towards understanding biological and molecular events impacting BMJ, especially regarding the role of extrahepatic UGT1A1 expression.