BACKGROUND: To investigate the effect of long-term smoking on the activity and mRNA expression of cytochrome P450 (CYP) enzymes. METHODS: Sprague-Dawley rats were exposed to passive smoking 6 cigarettes per day for 180 days. A cocktail solution which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), chlorzoxazone (20 mg/kg) and midazolam (10 mg/kg) was given orally to rats. Blood samples were collected at pre-specified time points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by DAS 3.0. In addition, real-time RT-PCR was used to analyze the mRNA expression of CYP1A2, CYP2C11, CYP2E1 and CYP3A1 in rat liver. RESULTS: There were no significant influences of pharmacokinetic profiles of chlorzoxazone in long-term smoking pretreated rats. But many pharmacokinetic profiles of phenacetin, tolbutamide, and midazolam in long-term smoking pretreated rats were affected significantly (P<0.05). The results suggested that long-term smoking had significant inhibition effects on CYP2C11 and CYP3A1 while CYP1A2 enzyme activity was induced. Furthermore, Long-term smoking had no effects on rat CYP2E1. The mRNA expression results were consistent with the pharmacokinetic results. CONCLUSIONS: Alterations of CYP450 enzyme activities may fasten or slow down excretion with corresponding influence on drug efficacy or toxicity in smokers compared to nonsmokers, which may lead to clinical failures of lung cancer therapy or toxicity in smokers.
BACKGROUND: To investigate the effect of long-term smoking on the activity and mRNA expression of cytochrome P450 (CYP) enzymes. METHODS:Sprague-Dawley rats were exposed to passive smoking 6 cigarettes per day for 180 days. A cocktail solution which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), chlorzoxazone (20 mg/kg) and midazolam (10 mg/kg) was given orally to rats. Blood samples were collected at pre-specified time points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by DAS 3.0. In addition, real-time RT-PCR was used to analyze the mRNA expression of CYP1A2, CYP2C11, CYP2E1 and CYP3A1 in rat liver. RESULTS: There were no significant influences of pharmacokinetic profiles of chlorzoxazone in long-term smoking pretreated rats. But many pharmacokinetic profiles of phenacetin, tolbutamide, and midazolam in long-term smoking pretreated rats were affected significantly (P<0.05). The results suggested that long-term smoking had significant inhibition effects on CYP2C11 and CYP3A1 while CYP1A2 enzyme activity was induced. Furthermore, Long-term smoking had no effects on ratCYP2E1. The mRNA expression results were consistent with the pharmacokinetic results. CONCLUSIONS: Alterations of CYP450 enzyme activities may fasten or slow down excretion with corresponding influence on drug efficacy or toxicity in smokers compared to nonsmokers, which may lead to clinical failures of lung cancer therapy or toxicity in smokers.
Authors: Anne-Joy M de Graan; Walter J Loos; Lena E Friberg; Sharyn D Baker; Jessica M van der Bol; Leni van Doorn; Erik A C Wiemer; Bronno van der Holt; Jaap Verweij; Ron H J Mathijssen Journal: Clin Cancer Res Date: 2012-05-29 Impact factor: 12.531
Authors: N Yasui; T Kondo; H Furukori; S Kaneko; T Ohkubo; T Uno; T Osanai; K Sugawara; K Otani Journal: Psychopharmacology (Berl) Date: 2000-06 Impact factor: 4.530
Authors: P H Villard; E M Seree; J L Re; M De Meo; Y Barra; L Attolini; G Dumenil; J Catalin; A Durand; B Lacarelle Journal: Toxicol Appl Pharmacol Date: 1998-02 Impact factor: 4.219
Authors: Yan S Ding; Jenna S Trommel; Xizheng J Yan; David Ashley; Clifford H Watson Journal: Environ Sci Technol Date: 2005-01-15 Impact factor: 9.028
Authors: Beth O Van Emburgh; Jennifer J Hu; Edward A Levine; Libyadda J Mosley; L Douglas Case; Hui-Yi Lin; Sommer N Knight; Nancy D Perrier; Peter Rubin; Gary B Sherrill; Cindy S Shaw; Lisa A Carey; Lynda R Sawyer; Glenn O Allen; Clara Milikowski; Mark C Willingham; Mark Steven Miller Journal: Mol Carcinog Date: 2008-02 Impact factor: 4.784