Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress

Abstract

Isothiocyanates, such as phenethyl isothiocyanate (PEITC), are formed following the consumption of cruciferous vegetables and generate reactive oxygen species (ROS) that lead to the induction of cytoprotective genes such as the UDP-glucuronosyltransferases (UGTs). The induction of ROS activates the Nrf2-Keap 1 pathway leading to the induction of genes through antioxidant response elements (AREs). UGT1A1, the sole enzyme responsible for the metabolism of bilirubin, can be induced following activation of Nrf2. When neonatal humanized UGT1 (hUGT1) mice, which exhibit severe levels of total serum bilirubin (TSB) because of a developmental delay in expression of the UGT1A1 gene, were treated with PEITC, TSB levels were reduced. Liver and intestinal UGT1A1 were induced, along with murine CYP2B10, a consensus CAR target gene. In both neonatal and adult hUGT1/Car−/− mice, PEITC was unable to induce CYP2B10. A similar result was observed following analysis of UGT1A1 expression in liver. However, TSB levels were still reduced in hUGT1/Car−/− neonatal mice because of ROS induction of intestinal UGT1A1. When oxidative stress was blocked by exposing mice to N-acetylcysteine, induction of liver UGT1A1 and CYP2B10 by PEITC was prevented. Thus, new findings in this report link an important role in CAR activation that is dependent upon oxidative stress.

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

“…In hUGT1 mice, oral administration of PEITC induced UGT1A1 expression in liver and small intestine, which led to a decrease in their serum bilirubin levels [91]. It was further demonstrated that the Cyp2b10 was also induced by the PEITC treatment in the liver and small intestine.…”

HumanizedUGT1Mice, Regulation ofUGT1A1, and the Role of the Intestinal Tract in Neonatal Hyperbilirubinemia and Breast Milk-Induced Jaundice

“…Sugatani et al (2001) first characterized the phenobarbital (Pb) responsive enhancer module in the human UGT1A1 gene that binds to the constitutive active receptor (CAR). When hUGT1 neonatal mice are treated with Pb, liver UGT1A1 is induced and TSB levels are dramatically reduced (Chen et al, 2012;Shibuya et al, 2013;Yoda et al, 2017;Yueh et al, 2017). However, in hUGT1/Car 2/2 mice, Pb administration does not induce UGT1A1 and has no impact on neonatal TSB levels, confirming genetically that CAR regulates the UGT1A1 gene.…”

“…However, in hUGT1/Car 2/2 mice, Pb administration does not induce UGT1A1 and has no impact on neonatal TSB levels, confirming genetically that CAR regulates the UGT1A1 gene. In hUGT1 mice, the UGT1A1 gene can be transcriptionally induced by other XNRs, including the pregnane X receptor (PXR) (Chen et al, 2012), the peroxisome proliferator-activated receptor alpha (PPARa) (Senekeo-Effenberger et al, 2007), the liver X receptors alpha and beta (LXRa/b; unpublished observations), and the environmental sensors, the aryl hydrocarbon receptor (AhR) (Yueh et al, 2003;Chen et al, 2005;Bonzo et al, 2007), and Nrf2 (Yueh and Tukey, 2007;Yoda et al, 2017). The oral or intraperitoneal administration of ligands capable of activating these receptors in neonatal hUGT1 mice leads to the Fig.…”

“…Untreated hUGT1/Ikkb DIEC mice displayed reduced intestinal UGT1A1 expression and elevated TSB levels, with most of the mice dying from SNH (Liu et al, 2016). When neonatal hUGT1 mice were orally treated with either Cd 2+ or As 3+ , intestinal UGT1A1 was induced and TSB levels were lowered (Liu et al, 2016;Yoda et al, 2017). Likewise, when hUGT1/Ikkb DIEC mice were treated with Cd 2+ or As 3+ , oxidative stress was induced in the intestines, commensurate with induction of UGT1A1 and a lowering of the TSB levels.…”

Isothiocyanates and Xenobiotic Detoxification

“…In rats fed a PEITC‐supplemented diet for two weeks, at the low dose corresponding to human dietary intake both quinone reductase and GST were elevated in the liver, and an increase in epoxide hydrolase activity was seen at higher doses; none of these activities was altered by the treatment in the lung, whereas in the kidney modest rises in quinone reductase and epoxide hydrolase occurred but only at higher doses, demonstrating tissue differences in the modulation of these enzymes by isothiocyanates . Oral administration of PEITC to humanized UGT 1 mice elevated UGT1A1 activity in the liver and intestine that led to a decrease in total serum bilirubin since this enzyme is responsible for the glucuronidation of bilirubin …”