Cigarette Smoke Extract Induces CYP2B6 through Constitutive Androstane Receptor in Hepatocytes

Washio, Ikumi; Maeda, Makiko; Sugiura, Chika; Shiga, Ryota; Yoshida, Mitsuhiro; Nonen, Shinpei; Fujio, Yasushi; Azuma, Junichi

doi:10.1124/dmd.110.034504

Cited by 41 publications

(23 citation statements)

References 15 publications

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“…Some CYP enzymes involved in the oxidation required to convert clopidogrel to its active form (15) are induced by smoking (16). Despite the “smoking paradox”, defined as the effect of smoking on clopidogrel conversion, smoking remains a strong independent risk factor for cardiovascular death (17).…”

Section: Discussionmentioning

confidence: 99%

High On-Treatment Platelet Reactivity in Danish Hyper-Acute Ischaemic Stroke Patients

2018

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Objective: Early anti-platelet therapy is a cornerstone in the prevention of recurrent ischaemic stroke (IS) and transient ischaemic attacks (TIAs), although the responsiveness to anti-platelet medications varies among patients. Several studies have reported that patients with ischaemic stroke who exhibit high on-treatment platelet reactivity (HTPR) 5–10 days after antiplatelet medication onset, have an increased risk of vascular events. In this study we aim to determine the prevalence of HTPR in the hyper-acute stroke phase less than 48 h from symptom onset, after the administration of a 300 mg bolus of oral clopidogrel in a real-world setting in Danish IS and TIA patients.Material and Methods: In total, 219 Danish patients with acute IS or TIA received 300 mg of oral clopidogrel on admission. Blood samples from all patients were analyzed using the VerifyNow P2Y12 system at 8–24 h after clopidogrel intake. Concomitant therapy and the intervals between ictus and blood collection, clopidogrel intake and blood collection, and blood sampling and analysis were recorded for all patients.Results: HTPR in the hyper-acute stroke phase was observed in 28.8% (63/219) samples. After adjustment for age, sex, co-morbidities, and co-medications, none of the tested variables exhibited an association with HTPR or the platelet reaction unit value measured using the VerifyNow P2Y12 system.Conclusions: The recognition of HTPR to specific anti-platelet agents in the hyper-acute phase after stroke may be the first step toward interventions that may further minimize the early recurrent stroke risk. Further large randomized trials including clinical outcome assessments are necessary.

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Section: Discussionmentioning

confidence: 99%

High On-Treatment Platelet Reactivity in Danish Hyper-Acute Ischaemic Stroke Patients

2018

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“…Clopidogrel is a prodrug that is converted to its active form in the liver via two metabolic steps involving CYP 1A2, 2B6, 2C9, 2C19, 3A4, and 3A5 (29,30). Among these CYP enzymes, it is known that smoking induces a higher activity of CYP 1A2 and 2B6 (31,32). Accordingly, it is thought that the active form of clopidogrel is increased in smokers resulting in more potent clopidogrel activity.…”

Section: Discussionmentioning

confidence: 99%

“…The induction of CYP2B6 by smoking involves the constitutive androstane receptor (CAR) (32,34). CAR, located in the cell cytoplasm, translocates into the nucleus when it is activated and there it forms heterodimers by binding to retinoid X receptor (RXR).…”

Section: Discussionmentioning

confidence: 99%

Relationship between Smoking and Responsiveness to Clopidogrel in Non-cardiogenic Ischemic Stroke Patients

et al. 2014

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Objective Clopidogrel is used to prevent the recurrence of non-cardiogenic ischemic stroke, but individual responsiveness to the drug varies. Moreover, it is known that smoking, which is a risk factor for ischemic stroke, affects the drug's pharmacokinetics. The objective of the present study was to investigate a possible relationship between smoking and responsiveness to clopidogrel in non-cardiogenic ischemic stroke patients. Methods The study involved 209 non-cardiogenic ischemic stroke patients who were administered oral clopidogrel at a dosage of 75 mg/day for at least 1 week. Platelet aggregation in response to adenosine diphosphate (20 μM) was measured in each patient using the VerifyNow P2Y12 Assay. Platelet aggregation and the incidence of resistance to clopidogrel were compared between a smokers group (70 patients) and a non-smokers group (139 patients). Clopidogrel resistance was defined as a P2Y12 Reaction Units (PRU) value >230 and/or % inhibition <20%. Results The mean PRU was 128.3±85.5 in the smokers group and 167.7±86.6 in the non-smokers group (p=0.002). The incidence of PRU >230 was 12.9% (9 patients) in the smokers group and 25.9% (36 patients) in the non-smokers group (p=0.033). The mean % inhibition was 48.6±30.7% in the smokers group and 36.9±27.6% in the non-smokers group (p=0.009). The incidence of patients with % inhibition <20% was 24.3% (17 patients) in the smokers group and 34.5% (48 patients) in the non-smokers group (p=0.155). Conclusion The incidence of clopidogrel resistance was lower in the non-cardiogenic ischemic stroke patients who were smokers, thus indicating that these patients' responsiveness to this drug may be enhanced.

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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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Cigarette Smoke Extract Induces CYP2B6 through Constitutive Androstane Receptor in Hepatocytes

Cited by 41 publications

References 15 publications

High On-Treatment Platelet Reactivity in Danish Hyper-Acute Ischaemic Stroke Patients

High On-Treatment Platelet Reactivity in Danish Hyper-Acute Ischaemic Stroke Patients

Relationship between Smoking and Responsiveness to Clopidogrel in Non-cardiogenic Ischemic Stroke Patients

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

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