Subacute nicotine co-exposure has no effect on 2,2′,3,5′,6- pentachlorobiphenyl disposition but alters hepatic cytochrome P450 expression in the male rat (original) (raw)
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Effect of side-stream cigarette smoke on the hepatic cytochrome P450
Archives of Environmental Contamination and Toxicology, 1993
The effect of inhalation of side-stream cigarette smoke on the hepatic microsomal cytochrome P450 was investigated. Rats were placed in a chamber of 0.1 m 3 in volume, in which cigarettes were burned at the rate of 1, 3, or 5 cigarettes per h, 8 h/day for 5 days. Cytochrome P450 and NADPHcytochrome c reductase showed no significant changes; however, cytochrome b 5 increased significantly. On the other hand, the activity of aryl hydrocarbon hydroxylase (AHH) decreased in the rats treated with a high concentration of cigarette smoke. In order to study the changes of isoforms of cytochrome P450, western blot analyses were performed. The inductions of three kinds of isoforms, cytochromes P450IA1, IA2, and liB 1, were demonstrated immunochemically. However, there were disagreements between the results of the western blot analyses and the measurements of total cytochrome P450 content and AHH activity.
Toxicological Sciences, 2001
Cigarette smoke is a complex mixture containing, among other chemicals, pyridine alkaloids and N-nitrosamines. Carcinogenic tobacco-specific N-nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are both activated by cytochrome P450 (CYP) 2E1 in rats. Previous reports indicate that nicotine and the main nicotine metabolite, cotinine, reduce the mutagenicity of both NNK and NDMA in Salmonella typhimurium. To study the mechanism of this effect, we examined inhibition of CYP 2E1 activity, as assessed by p-nitrophenol (pNP) hydroxylation, by nicotine, cotinine, and an aqueous cigarette tar extract (ACTE) in human 2E1-expressing microsomes. At all substrate concentrations (0 -1.25 mM) nicotine was a significantly more potent inhibitor of CYP 2E1 activity compared to cotinine. Estimated Ki values for nicotine and cotinine (both at 10 mM) were 13 mM (2 mg/ml) and 308 mM (54 mg/ml) respectively. The Ki for ACTE was 0.2 mg/ml at a concentration of 0.32 mg/ml. This rank order for inhibition was also seen when the data was expressed as IC 50 . When compared on a mass/vol basis, ACTE was a significantly more potent CYP 2E1 inhibitor relative to nicotine and cotinine. Double-reciprocal plots indicated that nicotine and ACTE inhibited by a competitive, while cotinine inhibited CYP 2E1 by an uncompetitive mechanism. Although the contribution of nicotine to ACTE-mediated 2E1 inhibition is probably modest, pyridine alkaloid-mediated CYP 2E1 inhibition is a possible mechanism for the observed inhibition of NNK and NDMA mutagenicity by nicotine and cotinine in vitro.
Characterization of b-nicotyrine-mediated inactivation of cytochrome P450 2A6
2013
Nicotine, the primary addictive compound in cigarettes, is metabolized in humans by cytochrome P450 2A enzymes. The hepatic enzyme responsible for the metabolism of nicotine in smokers is P450 2A6. P450 2A13, which shares 94% primary sequence homology with P450 2A6, also catalyzes the metabolism of nicotine and is present in the lung. Loss of P450 2A activity is correlated with modified smoking behavior and addiction. Inhibition of these enzymes decreases nicotine metabolism and may be of benefit in smoking cessation. This thesis investigates tobacco-related molecules that may impact P450 2A function and is presented in three parts. In the first, the potential inhibitory potency of (-)-menthol, (R)-(+)-menthofuran, and -nicotyrine of both P450s 2A6 and 2A13 are investigated. All three compounds inhibit P450 2A6 and 2A13 activity. In addition, menthofuran and -nicotyrine mediate mechanism-based inactivation of P450 2A6 but not 2A13. Second, the P450 2A6 and P450 2A13-mediated metabolism of -nicotyrine is studied and three metabolites are identified. -nicotyrine is readily turned over by both P450 2A6 and P450 2A13 as indicated by the calculated K m (4.4µM and 5.0µM, respectively) and V max (21 and 37 pmol product/min/pmol, respectively) values. Also in the second section, -nicotyrine is shown to be a metabolite of P450 2A6-mediated nicotine metabolism. In the last section, attempts to identify a covalent adduct that would result from menthofuran or -nicotyrine-mediated inactivation are presented, but these are largely unsuccessful.
Molecular pharmacology, 2003
Nicotine metabolism is decreased in smokers compared with nonsmokers, but the mechanism(s) responsible for the slower metabolism are unknown. Nicotine is inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)]. CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6. To evaluate the effects of long-term nicotine treatment on hepatic levels of CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine-treated animals. A CYP2B6-like protein (CYP2B6agm)...
Journal of Pharmacology …, 2003
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