Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Department of Pharmacology, University of Toronto, Canada.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 10/2003; 306(3):941-7. DOI: 10.1124/jpet.103.052183
Source: PubMed


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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Available from: Edward M Sellers, Nov 16, 2015
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    • "Cyp2e1 gene was upregulated only marginally (Figure 19). Activity of the Cyp2E1 enzyme has been reported to be induced in rat livers by nicotine, but this upregulation appeared to occur at the post-transcriptional level (Howard et al., 2001; Joshi & Tyndale, 2006; Micu et al., 2003). For Acox1 and Ugt1a1, only very weak increases could be seen. "
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    ABSTRACT: Toxicity of nebulized nicotine (Nic) and nicotine/pyruvic acid mixtures (Nic/Pyr) was characterized in a 28-day Organization for Economic Co-operation and Development 412 inhalation study with additional transcriptomic and lipidomic analyses. Sprague-Dawley rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, saline, nicotine (50 µg/l), sodium pyruvate (NaPyr, 33.9 µg/l) or equimolar Nic/Pyr mixtures (18, 25 and 50 µg nicotine/l). Saline and NaPyr caused no health effects, but rats exposed to nicotine-containing aerosols had decreased body weight gains and concentration-dependent increases in liver weight. Blood neutrophil counts were increased and lymphocyte counts decreased in rats exposed to nicotine; activities of alkaline phosphatase and alanine aminotransferase were increased, and levels of cholesterol and glucose decreased. The only histopathologic finding in non-respiratory tract organs was increased liver vacuolation and glycogen content. Respiratory tract findings upon nicotine exposure (but also some phosphate-buffered saline aerosol effects) were observed only in the larynx and were limited to adaptive changes. Gene expression changes in the lung and liver were very weak. Nic and Nic/Pyr caused few significant changes (including Cyp1a1 gene upregulation). Changes were predominantly related to energy metabolism and fatty acid metabolism but did not indicate an obvious toxicity-related response. Nicotine exposure lowered plasma lipids, including cholesteryl ester (CE) and free cholesterol and, in the liver, phospholipids and sphingolipids. Nic, NaPyr and Nic/Pyr decreased hepatic triacylglycerol and CE. In the lung, Nic and Nic/Pyr increased CE levels. These data suggest that only minor biologic effects related to inhalation of Nic or Nic/Pyr aerosols were observed in this 28-day study.
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    • "For each animal, two timed blood samples were obtained from the saphenous vein and the third sample from trunk blood at time of sacrifice. The sample timing and animal numbers were based on previous nicotine studies performed in our laboratory in adult rats, e.g., Micu et al. (2003), and pilot s.c. nicotine injection studies performed in adolescent rats. "
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    ABSTRACT: Several behavioral studies report that adolescent rats display a preference for nicotine compared to adults. However, age-related pharmacokinetic differences may confound the interpretation of these findings. Thus, differences in pharmacokinetic analyses of nicotine were investigated. Nicotine was administered via acute subcutaneous (1.0 mg base/kg) or intravenous (0.2 mg base/kg) injection to early adolescent (EA; PND25) and adult (AD; PND71) male Wistar rats. Nicotine and its primary metabolite cotinine, and additional metabolites nornicotine, nicotine-1'-N-oxide, trans-3'-hydroxycotinine and norcotinine were sampled from 10 minutes to 8 hours (plasma) and 2 to 8 hours (brain) post nicotine and analyzed by LC-MS/MS. Following subcutaneous nicotine, the EA cohort had lower levels of plasma nicotine, cotinine and nicotine-1'-N-oxide at multiple time points, resulting in a lower area under the plasma concentration-time curve (AUC) for nicotine (p<0.001), cotinine (p<0.01) and nicotine-1'-N-oxide (p<0.001). Brain levels were also lower for these compounds. In contrast, the EA cohort had higher plasma and brain AUCs (p<0.001) for the minor metabolite nornicotine. Brain to plasma ratios varied for nicotine and its metabolites, and by age. Following intravenous nicotine administration similar age-related differences were observed, and this route allowed detection of a 1.6-fold larger volume of distribution and 2-fold higher plasma clearance in EA cohort compared to AD cohort respectively. Thus, unlike in humans, there are substantial age differences in nicotine pharmacokinetics such that for a given nicotine dose, adolescent rats will have lower plasma and brain nicotine compared to adults suggesting that this should be considered when interpreting animal model data.
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    • "involve an increase in translational efficiency (Wu et al., 1997; Micu et al., 2003). Thus, ethanol and nicotine may increase CYP2E1 in monkey liver using post-transcriptional mechanisms similar to those observed for rat liver CYP2E1. "
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    ABSTRACT: Cytochrome P450 2E1 metabolizes ethanol and also bioactivates many toxins and procarcinogens. Elevated levels of hepatic CYP2E1 are associated with an increased susceptibility to chemical toxicity and carcinogenesis. This study investigated the induction of hepatic CYP2E1 by ethanol and nicotine, alone and in combination, in a nonhuman primate model. Monkeys that self-administered ethanol and that received subcutaneous injections of nicotine (0.5 mg/kg b.i.d.), alone and in combination, were compared with control animals (four groups, n = 10/group). Chlorzoxazone (CZN) was used as a probe drug to phenotype in vivo CYP2E1 activity before and after chronic ethanol and/or nicotine exposure. CYP2E1 protein levels and in vitro chlorzoxazone metabolism were assessed in liver microsomes. Average daily ethanol consumption was ≈3.0 g/kg (blood ethanol levels ≈24 mM) and was unaffected by nicotine treatment. Ethanol self-administration and nicotine treatment, alone and in combination, significantly increased in vivo CZN disposition compared with that in control animals. The effect of ethanol was only observed at higher levels of intake. Ethanol and nicotine increased CYP2E1 protein levels and in vitro CZN metabolism, with combined exposure to both drugs resulting in the greatest increase. The effect of ethanol was also dependent on level of intake. Chronic exposure to ethanol and nicotine induced hepatic CYP2E1 activity and protein levels, particularly when both drugs were used in combination and when ethanol intake was high. These results have important implications for public health, given the association between elevated CYP2E1 and disease, and the large proportion of individuals who are exposed to ethanol and nicotine, often in combination.
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