title: Auto-Induction Effect of Chloroxoquinoline on the Cytochrome P450 Enzymes of Rats Associated with CYP 3A and 1A.
abstract: To investigate the auto-induction of cytochrome P450 (CYP450) by Chloroxoquinoline (CXL), a novel anticancer drug. Three experiments related to the induction of CYP450 were performed: a) In vitro use of the rat fresh hepatocytes model; b) In vivo 'cocktail' of CYP450 probe model; c) Pharmacokinetic (PK) study of the single and multiple doses. Some typical CYP enzyme probes and inducers were used in these experiments and were all determined by HPLC-MS/MS. The expression levels of CYP3A and CYP1A mRNA were analyzed by the real time polymerase chain reaction (RT-PCR) technique. The PK studies showed that the area under the curve (AUC0-t) and the peak concentration (Cmax) of the multiple doses were approximately 2.4-fold and 1.9-fold lower than those of the single dose, respectively (p < 0.05). Subsequent studies were conducted to study the possible induction of CXL on CYP 450. The in vivo 'cocktail' administration of CYP450 probe model indicated that 5 d pretreatment with CXL resulted in a mean 4.6 times increase in the metabolites/probe plasma ratios for CYP 3A and a 336% increase for CYP 1A than those of the negative control (p < 0.05). The induction effect of CXL on CYP450 was further evaluated on rat hepatocytes with four concentrations (1, 10, 50 and 100 μmol/L). Compared with the negative control, the mRNA levels of CYP 1A2 increased significantly in rat hepatocytes after treatment with 10, 50 and 100 μmol/L CXL (p < 0.05). While significant inductions of CYP 3A1 were observed in the entire treated groups. The results of the present study demonstrate enhanced and induced expression of CYP 3A and CYP 1A in response to CXL exposure in rats, suggesting that CXL is an auto-inducer of CYP 3A and CYP 1A.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China; Department of Pharmacy, Chinese PLA General Hospital, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Mei Yan
authors.initials: MY
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Zhi Ping
authors.initials: ZP
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yu Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Zhen Qing
authors.initials: ZQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D065694:Cytochrome P-450 CYP1A2 Inducers / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000493:pharmacokinetics / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D065694:Cytochrome P-450 CYP1A2 Inducers; D065701:Cytochrome P-450 CYP3A Inducers; D011804:Quinolines; C543063:chloroxoquinoline; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A