Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.
ABSTRACT CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. x 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. x 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (x 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg x 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).
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ABSTRACT: 1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats.Xenobiotica 06/2014; · 1.98 Impact Factor
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ABSTRACT: Lung cancer is the most common cause of cancer-related deaths worldwide. The aim of this study was to investigate the association of five extensively-studied polymorphisms in PTGS2 (rs689466, rs5275, rs20417) and CYP2E1 (rs2031920, rs6413432) genes with lung cancer risk in a large northeastern Chinese population. This is a hospital-based case-control study involving 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR method. Data were analyzed using Haplo.stats and MDR programs. There were significant differences between patients and controls in allele/genotype distributions of rs5275 (P = 0.002/0.003) and rs6413432 (P = 0.037/0.044), as well as in genotype distributions of rs689466 (P = 0.02). The risk for lung cancer associated with the rs5275-C mutant allele was decreased by 60% (95% CI [confidence interval]: 0.21-0.74; P = 0.004) under the recessive model. Carriers of rs689466-G mutant allele had a 28% (95% CI: 0.57-0.92; P = 0.008) reduced risk of developing lung cancer relative to the AA genotype carriers. In haplotype analysis, haplotype G-C-C-T (in order of rs689466, rs5275, rs2031920 and rs6413432) decreased the odds of lung cancer by 28% (95% CI: 0.51-0.93; P = 0.019) after adjusting for confounding factors, whereas haplotype A-T-T-T had 1.49-fold (95% CI: 1.21-1.79; P = 0.012) increased risk for lung cancer. Using MDR method, the overall best model including rs5275, rs689466 and rs6413432 polymorphisms was identified with a maximal testing accuracy of 66.1% and a maximal cross-validation consistency of 10 out of 10 (P = 0.003). Our findings demonstrated a potentially synergistic association of PTGS2 and CYP2E1 polymorphisms with the underlying cause of lung cancer in northeastern Chinese.PLoS ONE 01/2012; 7(6):e39814. · 3.53 Impact Factor
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ABSTRACT: The purpose of this report is to summarize the roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma (HCC). Chronic heavy alcohol exposure is a major risk factor for HCC, which is the most frequent type of liver cancer. Alcohol ingestion may initiate and or promote the development of HCC by: 1) acetaldehyde-DNA adduct formation; 2) cytochrome P4502E1-associated reactive oxygen species (ROS) generation , lipid peroxidation, p53 mutation, and conversion of pro-carcinogens to carcinogens; 3) iron accumulation that leads to ROS generation, lipid peroxidation, p53 mutation, and initiation of inflammatory cascade via nuclear factor-KappaB (NF-kB) activation; 4) glutathione depletion leading to oxidative stress; 5) s-adenosylmethionine (SAM) depletion and associated DNA hypomethylation of oncogenes ; 6) retinoic acid depletion and resultant hepatocyte proliferation via up-regulation of activator protein-1 (AP-1); 7) initiating an inflammatory cascade through increased transfer of endotoxin from intestine to liver, Kupffer cell activation via CD14/toll-like receptor-4 (TLR-4), oxidative stress, NF-kB or early growth response-1(Egr-1) activation, and generation of inflammatory cytokines and chemokines; 8) induction of liver fibrosis; and 9) decreasing the number and/or function of Natural Killer cells. Tobacco exposure is also a risk factor for HCC. It may contribute to the initiation and promotion of HCC due the presence of mutagenic and carcinogenic compounds as well as by causing oxidative stress due to generation of ROS and depletion of endogenous antioxidants. Simultaneous exposure to alcohol and tobacco is expected to promote the development of HCC in an additive and/or synergistic manner.Life sciences 10/2012; · 2.56 Impact Factor