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. ϫ 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. ϫ 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 (ϫ 7 days) nicotine with an ED 50 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 ϫ 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).

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

“…The mechanism(s) underlying these associations are unknown. The results from this study demonstrate for the first time that nicotine exposure alone, at concentrations which are representative of human exposure [17,18], during pregnancy and lactation results in endocrine and metabolic changes in the offspring that are consistent with the disturbed glucose metabolism that may lead to type 2 diabetes. In the present study we have shown that fetal and neonatal exposure to nicotine results in impaired glucose homeostasis in response to a glucose challenge prior to a measurable difference in body weight (7 weeks of age), suggesting that in this model the metabolic changes associated with the onset of type 2 diabetes precede obesity.…”

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

“…The livers were removed immediately and stored at −80 °C. In our previous studies, subcutaneous nicotine injections of 1.0 mg base/kg for 7 days lead to significant increases in hepatic CYP2E1 protein levels (Howard et al, 2001;Micu et al, 2003) while having no effect on CYP2B levels (Miksys et al, 2000a); 18 days of nicotine treatment did not further increase hepatic CYP2E1 over levels seen after 7 days treatment (Micu et al, 2003).…”

“…Alcohol and nicotine are commonly co-abused (Batel et al, 1995), and the individual use of both these drugs alters hepatic levels of cytochrome P450 enzymes (Schoedel et al, 2001); (Micu et al, 2003;Schoedel and Tyndale, 2003). Increases in hepatic CYP2E1 and CYP2B enzymes can alter the metabolism of clinical drugs and toxins and may play a role in the increase in ethanol consumption seen in the presence of chronic nicotine treatment.…”

“…The induction of both hepatic and cerebral CYP2E1 by chronic nicotine treatment is post-transcriptional which may be due to the protein stabilization or translational activation (Howard et al, 2001;Joshi and Tyndale, 2006). Thus, ethanol and chronic nicotine can induce hepatic CYP2E1 via post-transcriptional methods, although while ethanol may stabilize the CYP2E1 protein (Roberts et al, 1995), nicotine does not (Micu et al, 2003). …”

“…Rats will self-administer between 0.15 and 1.5 mg/kg of nicotine within self-administration sessions lasting 1-2 h (Matta et al, 2007), while human smokers, which are slower nicotine metabolizers than rats, consume approximately 0.5 mg/kg/day (Benowitz and Jacob, 1984). Together with plasma concentration data (Micu et al, 2003), this suggests that the doses used in this study are similar to the nicotine acquired from smoking approximately 10 cigarettes (Le Houezec et al, 1993). The rats voluntarily consumed between 0.4 and 1.5 g/kg of ethanol per day resulting in estimated peak ethanol levels of around 50-120 mg/dl (Buczek et al, 1997), which would be similar to plasma levels achieved in humans after 1-5 standard drinks (social drinking) (Wilkinson et al, 1977).…”