A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers

Schrenk, Dieter; Brockmeier, D.; Mörike, Klaus; Bock, Karl Walter; Eichelbaum, Michel

doi:10.1007/s002280050394

Cited by 104 publications

(58 citation statements)

References 19 publications

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“…Many schizophrenic patients are smokers. Among smokers, CYP1A2 MR shows a trend toward a bimodal distribution (i.e., with the existence of a "nonresponder" phenotype concerning CYP1A2 induction by compounds present in tobacco smoke) in both white persons and Asians (Nakajima et al, 1994;Schrenk et al, 1998). The Ϫ164CϾA SNP has been suggested to be associated with higher enzyme inducibility in white smokers (Sachse et al, 1999) and the Ϫ3858GϾA (CYP1A2*1C) with decreased enzyme inducibility in Japanese smokers (Nakajima et al, 1999).…”

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confidence: 99%

Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1

Aklillu¹,

Carrillo²,

Makonnen³

et al. 2003

Mol Pharmacol

149

108

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CYP1A2 polymorphism has been well studied in white persons and Asians but not in Africans. We performed CYP1A2 genotype and phenotype analysis using caffeine in Ethiopians living in Ethiopia (n ϭ 100) or in Sweden (n ϭ 73). We sequenced the CYP1A2 gene using genomic DNA from 12 subjects, which revealed a novel intron 1 single-nucleotide polymorphism (SNP), Ϫ730CϾT. We developed SNP-specific polymerase chain reaction-restriction fragment length polymorphism genotyping and molecular haplotyping methods for the intron 1 SNPs, and four different haplotypes were identified: CYP1A2*1A (wild-type for all SNPs), CYP1A2*1F (Ϫ164A), CYP1A2*1J (Ϫ740G and Ϫ164A), and CYP1A2*1K (Ϫ730T, Ϫ740G, and Ϫ164A), having frequencies of 39.9, 49.6, 7.5, and 3.0%, respectively. The frequency of CYP1A2*1J and CYP1A2*1K among Saudi Arabians (n ϭ 136) was 5.9% and 3.6%, and among Spaniards (n ϭ 117) 1.3% and 0.5%, respectively. Functional significance of the different intron 1 haplotypes was analyzed. Subjects with CYP1A2*1K had significantly decreased CYP1A2 activity in vivo, and reporter constructs with this haplotype had significantly less inducibility with 2,3,7,8-tetrachlorodibenzo-p-dioxin in human B16A2 hepatoma cells. Electrophoretic mobility shift assay using nuclear extracts from B16A2 cells revealed a specific DNA binding protein complex to an Ets element. Efficient competition was obtained using oligonucleotide probes carrying the wt sequence and Ets consensus probe, whereas competition was abolished using probes with the Ϫ730CϾT SNP alone or in combination with Ϫ740TϾG (CYP1A2*1K). The results indicate a novel polymorphism in intron 1 of importance for Ets-dependent CYP1A2 expression in vivo and inducibility of the enzyme, which might be of critical importance for determination of interindividual differences in drug metabolism and sensitivity to carcinogens activated by CYP1A2.

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confidence: 99%

Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1

Aklillu¹,

Carrillo²,

Makonnen³

et al. 2003

Mol Pharmacol

149

108

View full text Add to dashboard Cite

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“…In addition, smoking cause alterations of pharmacokinetics and drug interactions (Kroon 2007;Li and Shi 2015;Smith 2009). This has been primarily related to induction of liver detoxifying enzymes, including cytochrome P-450 (CYP) 1A1, CYP1B1, CYP1A2, CYP2B6 and glutathione S-transferases, by cigarette smoke chemicals (Chang et al 2003;Eke and Iscan 2002;Schrenk et al 1998;Washio et al 2011). This results in increased metabolism of drugs like imipramine, meprobamate, oestrogens, pentazocine, phenylbutazone, theophylline and warfarin (Miller 1989).…”

Section: Introductionmentioning

confidence: 99%

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

et al. 2016

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Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummarySmoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG ce...

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“…Elevated levels of these enzymes, resulting either from a genetic polymorphism or from exposure to an inducer, i.e., an AHR ligand, might predispose individuals to cancer. Interindividual differences in CYP1A1 and CYP1A2 activity have been previously reported in several studies (Butler et al 1992;Smart and Daly 2000;Schrenk et al 1998).…”

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confidence: 53%

Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene

et al. 2002

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A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers

Cited by 104 publications

References 19 publications

Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1

Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene

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