Effect of nicotine on cytochrome P450 1A2 activity

Abstract

Cigarette smoking accelerates the metabolism of certain drugs, particularly those primarily metabolized by cytochrome P450 1A2 (CYP1A2) and, to a lesser extent, CYP2E1 and some UDP-glucuronosyltransferases [1,2]. The induction of CYP1A2 is mediated by binding of polycyclic aromatic hydrocarbons of the tobacco smoke to the aryl hydrocarbon receptor (AHR) with consequent transcriptional activation of the CYP1A2 gene. Furthermore, CYP1A1 and CYP1B1 enzymes are induced by tobacco smoking via AHR in various human tissues such as lung and placenta [3]. As CYP1A1 and CYP1B1 are mostly expressed in extrahepatic tissues, their induction by smoking is not known to affect the pharmacokinetics of any medication. There is evidence of the role of nicotine in the induction of CYP1A1 and CYP1A2 enzymes in vitro in rat lung [4], and in vivo in rat lung, kidney and liver [5][6][7], liver and placenta of pregnant rats [8] and in brains of mice and rats [9,10], probably through mechanisms not involving AHR. Some evidence exists for the induction of CYP1A1 by nicotine in human pulmonary explant culture [11].We recently published a study on the effects of 10 day dosing of nicotine on human CYP2A6 and CYP2E1 activities [12]. An additional aim of that study was to determine the effects of high dose nicotine on the pharmacokinetics of oral caffeine and to test the hypothesis that nicotine induces CYP1A2-mediated metabolism of caffeine to paraxanthine, a well-established probe reaction of CYP1A2 activity [13]. No previous study has studied the effects of nicotine on CYP1A2 activity in humans in vivo.The details of the experimental protocol and the subject characteristics are described in a prior report [12]. Briefly, 12 healthy smokers were given two 21 mg transdermal patches delivering a total of 42 mg nicotine day -1 or placebo patches, each for 10 days in a randomized and crossover design. Subjects were not allowed to smoke or to use any tobacco products during hospitalization. At noon on the eighth hospital day, 200 mg of oral caffeine was given. Blood samples were collected for measurement of caffeine and metabolites at 0, 30 and 60 min, and then 2, 3, 4, 6, 8, 12, 20, 32, 44 and 52 h after ingestion of caffeine. In addition, deuterium-labelled nicotine-D2 and cotinine-D4 phenotyping for CYP2A6, bupropion phenotyping for CYP2B6 and chlorzoxazone phenotyping for CYP2E1 were performed on the seventh and eighth hospital days as previously described [12].Concentrations of caffeine, paraxanthine, theobromine and theophylline in plasma were determined using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Stable isotope-labelled analogues of paraxanthine and caffeine were used as internal standards. Following protein precipitation, samples (0.2 ml) were treated with phosphate buffer and extracted with a mixture of methylene chloride, ethyl acetate and isopropyl alcohol. The extracts were evaporated, reconstituted in the LC mobile phase, and injected into the LC-MS/MS system. The mass spectrometer was operated using ...

Does coffee consumption impact on heaviness of smoking?

“…Inhibition of CYP2A6‐mediated nicotine metabolism by constituents of coffee prolongs nicotine's clearance may be similar to the established impact of reduced nicotine metabolizer phenotype on reducing smoking in these smoking coffee consumers 20. It is known that smoking induces the enzyme cytochrome P450 1A2 (CYP1A2) (the main enzyme involved in caffeine metabolism), and therefore increases metabolism of caffeine 21, 22. It is also possible that constituents of coffee may have a pharmacological impact on the actions or metabolism of nicotine 1.…”

Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis

“…12,14 CYP1A2 is the primary enzyme responsible for metabolizing caffeine, whilst AHR controls transcription of CYP1A2. 15 Combining variants in these regions into a multiple allelic genetic risk score increases the proportion of variance in caffeine consumption explained and hence increases power. 10 It is important to note that these variants are likely to affect consumption through their effects on caffeine metabolism (i.e., slow metabolism of caffeine results in reduced consumption), so these instruments may have opposing effects on blood caffeine levels; the allele in AHR which increases coffee consumption was associated with lower blood caffeine in a GWAS of blood metabolites.…”

“…Two key genetic loci are close to the cytochrome P450 1A1/2 ( CYP1A1/CYP1A2 ) and aryl hydrocarbon receptor ( AHR ) genes, which are known to play a functional role in caffeine metabolism . CYP1A2 is the primary enzyme responsible for metabolizing caffeine, whilst AHR controls transcription of CYP1A2 . Combining variants in these regions into a multiple allelic genetic risk score increases the proportion of variance in caffeine consumption explained and hence increases power .…”

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

“…The one exception to this generalization was that exposure to nicotine for 3 d, but not 1 or 7 d, downregulated hippocampal CYP1A2 expression. Evidence for CY1A2 transcriptional regulation by nicotine in liver and/or brain has been shown in rodents (Anandatheerthavarada et al, 1993b; Price et al, 2004), although in humans, nicotine has been reported to have no effect on CYP1A2 activity (Hukkanen et al, 2011). CYP1A2 has been implicated in PCB metabolism (Fitzgerald et al, 2005; Zhou et al, 2010; Curran et al, 2011); however, whether its transient downregulation in the hippocampus is functionally relevant to PCB neurotoxicity has yet to be determined.…”