title: Pretreatment with turmeric modulates the inhibitory influence of cisplatin and paclitaxel on CYP2E1 and CYP3A1/2 in isolated rat hepatic microsomes.
abstract: Previous animal studies have shown that turmeric can significantly modulate the activity of several drug metabolizing enzymes, this may dramatically affect the bioavailability of several drugs resulting in over dose or less therapeutic effects. This study was directed to evaluate the inhibitory effects of cisplatin and paclitaxel on two CYP450 enzymes namely CYP2E1 and CYP3A1/2 in hepatic microsomes isolated from normal and turmeric pretreated rats. Cisplatin and paclitaxel were added by different concentrations to hepatic microsomes isolated from untreated and turmeric (100 mg/kg/day) pretreated rats for 15 days after receiving pyrazole or dexamethasone for induction of CYP2E1 and CYP3A1/2 respectively. The kinetic potency of these drugs as CYP inhibitors was determined by analysis of Lineweaver-Burk plot. Addition of cisplatin or paclitaxel by (10, 50 and 100 μM) to hepatic microsomes from normal or turmeric pretreated rats caused a concentration dependent inhibition of CYP2E1, with an evidence of less inhibition in turmeric pretreated microsomes particularly at higher concentration. Both drugs at 100 μM displayed a mixed type of inhibition of CYP2E1 in normal or turmeric pretreated microsomes where paclitaxel was the most potent inhibitor. Cisplatin (10, 50 and 100 μM) caused a concentration dependant inhibition of CYP3A1/2 that was enhanced by turmeric pretreatment. The inhibition of CYP3A1/2 by cisplatin (100 μM) was in non-competitive manner with a smaller Ki value in turmeric pretreated microsomes. The inhibitory influence of paclitaxel (10, 50 and 100 μM) on CYP3A1/2 decreased with increasing the drug concentration and this inhibition was augmented by turmeric pretreatment. Interestingly, the inhibition of this enzyme by paclitaxel (10 μM) was switched from mixed type in normal microsomes to competitive manner in turmeric pretreated ones with a marked reduction of Ki values reflecting greater inhibitory influence of paclitaxel on CYP3A1/2 by turmeric pretreatment. In conclusion, turmeric pretreatment attenuated the inhibitory influence of cisplatin and paclitaxel on CYP2E1 activity and magnified their inhibition on CYP3A1/2, thus the use of turmeric with drugs or other medications should raise concern for drugs-herb interactions.
authors.affiliation: Biochemistry & Molecular Biology Department, National Organization for Drug Control & Research, Egypt.
authors.forename: Enas M
authors.initials: EM
authors.lastname: Ahmed
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: Shohda.elmaraghy@pharma.cu.edu.eg.
authors.forename: Shohda A
authors.initials: SA
authors.lastname: EL-Maraghy
authors.affiliation: Biochemistry & Molecular Biology Department, National Organization for Drug Control & Research, Egypt.
authors.forename: Zakaria A
authors.initials: ZA
authors.lastname: Teleb
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Amira A
authors.initials: AA
authors.lastname: Shaheen
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D030024:Curcuma; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology*; D028321:Plant Preparations / Q000494:pharmacology*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D028321:Plant Preparations; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel; D002945:Cisplatin
keywords: CYP450 isoenzyme; Cisplatin; Inhibition; Paclitaxel; Turmeric