Effect of orally administered phenethyl isothiocyanate on hepatic gene expression in rats

Abstract

Phenethyl isothiocyanate (PEITC) is a constituent of cruciferous vegetables that has demonstrated cancer preventive activity in a number of cancer models including lung, prostate, and breast cancer. Our objective was to examine the effects of the oral administration of PEITC for 7 days on the hepatic expression of genes important in drug metabolism and toxicity in Sprague Dawley rats. The liver is the major site for the metabolism of various xenobiotics and carcinogens, and determining the effects of PEITC on the gene expression of hepatic enzymes may provide insight into mechanisms underlying the cancer preventive activity of PEITC. Using a microarray containing 282 genes, we observed that PEITC significantly up-regulated UDP-glucuronosyltransferase UGT1A6 and strongly down-regulated nicotinamide N-methyltransferase (NNMT). We also confirmed the down-regulation of NNMT by real-time quantitative RT-PCR. NNMT was recently shown to be elevated in the serum of tumor bearing patients with pancreatic, lung, and colorectal cancer, and may be involved in cell migration. Other genes that were significantly up-regulated were the drug metabolizing enzyme cyp2b15, the anti-apoptotic gene bcl2l2, and the stress regulators Gadd45b, Dnajb9, Dnajb5 and Hspb1. Our results indicate new targets that may be important in the mechanisms of the anticancer effects of PEITC. Of particular significance was the down-regulation of NNMT which may represent a new target for the treatment of a variety of cancers.

Phenethyl isothiocyanate and indole‐3‐carbinol from cruciferous vegetables, but not furanocoumarins from apiaceous vegetables, reduced PhIP‐induced DNA adducts in Wistar rats

“…This reduction is consistent with the reduction of methylated PhIP metabolites by feeding intact cruciferous vegetables [15], and the finding that PEITC downregulates gene expression of N-methyl transferases (NMTs) [40]. This decrease in methylated metabolites is likely due to increases in conjugation and formation of CYP1A-mediated PhIP metabolites, which would channel available PhIP in the system away from the methylation pathway; downregulation of NMTs by PEITC possibly contributed to this as well [40]. Therefore, the apparent protective effect achieved by the P + I is probably independent from methylation of PhIP.…”

Chemopreventive and anti‐angiogenic effects of dietary phenethyl isothiocyanate in an N‐methyl nitrosourea‐induced breast cancer animal model

“…Our histologic evaluations of the formed tumors suggest that the control and low dose PEITC groups demonstrated the presence of invasive tumors, while the 150 µmol/kg group did not show any invasive tumors. A dose of 150 µmol/kg PEITC can down‐regulate NNMT , which may play a role in this observed reduction in invasiveness. Additionally, the intratumoral capillary density was lower in both the PEITC treatment groups, compared with the control groups.…”

“…It was demonstrated previously that at 150 µmol/kg doses in female rats, PEITC can up‐regulate the enzyme UDP‐glucuronosyltransferase 1a (ugt1a) and down‐regulate NNMT, an enzyme shown recently to be an important prognostic marker that may play a role in tumor cell migration and invasiveness . Based on simulations from a pharmacokinetic model published previously , this dose yields maximal plasma concentrations of about 100 µ m .…”

Nutraceuticals and Cancer

“…N-nitrosomethylbenzylamineinduced changes in gene expression in rat esophagus were positively modulated to normal levels of expression by PEITC administration (Stoner et al 2008). PEITC administration was found to significantly up-regulate UDP-glucuronosyltransferase 1A6 and strongly down-regulate nicotinamide N-methyltransferase (Telang and Morris 2010). PEITC administration was found to significantly up-regulate UDP-glucuronosyltransferase 1A6 and strongly down-regulate nicotinamide N-methyltransferase (Telang and Morris 2010).…”

“…Effect of oral administration of PEITC for 7 days on the hepatic expression of genes important in drug metabolism and toxicity was studied using Sprague Dawley rats (Telang and Morris 2010). Other significantly upregulated genes included CYP2b15, the anti-apoptotic gene Bcl2l2, and the stress regulators Gadd45b, Dnajb9, Dnajb5 and Hspb1 (Telang and Morris 2010). Other significantly upregulated genes included CYP2b15, the anti-apoptotic gene Bcl2l2, and the stress regulators Gadd45b, Dnajb9, Dnajb5 and Hspb1 (Telang and Morris 2010).…”