Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells

• Published in: European journal of clinical pharmacology Vol. 58; no. 8; pp. 537 - 542
• Main Authors: BAPIRO, Tashinga E, ANDERSSON, Tommy B, OTTER, Charlotta, HASLER, Julia A, MASIMIREMBWA, Collen M
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01-11-2002; Berlin Springer Nature B.V
• Subjects: Albendazole - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiparasitic Agents - pharmacology; Antiparasitic Agents - toxicity; Biological and medical sciences; Cell Survival - drug effects; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A2 - biosynthesis; Dose-Response Relationship, Drug; Enzyme Induction; Humans; Medical sciences; Medicin och hälsovetenskap; Pharmacology. Drug treatments; Polychlorinated Dibenzodioxins - metabolism; Polychlorinated Dibenzodioxins - toxicity; Primaquine - pharmacology; Quinine - pharmacology; RNA, Messenger - biosynthesis; Tumor Cells, Cultured; Human; Cytochrome P450; CYP1A induction; Hepatic disease; Exploration; Malignant tumor; Metabolism; Quinine; Dose activity relation; Cell line; Messenger RNA; Albendazole; Enzymatic activity; Parasiticid; Digestive diseases; Hepatoblastoma
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-002-0512-z

To investigate the inductive effects of twenty-four antiparasitic drugs on cytochrome P450 (CYP) 1A1 and 1A2 enzyme activities.
Human hepatoma (HepG2) cells were exposed to antiparasitic drugs for 24 h, and the ethoxyresorufin O-deethylase (EROD) activity, indicative of CYP1A enzyme activity, was measured fluorometrically. In addition, the CYP1A1 and CYP1A2 mRNA expression levels were determined by means of quantitative reverse-transcriptase polymerase chain reaction.
Quinine, albendazole and primaquine caused a dose-dependent increase in EROD activity of 5.5, 4.0 and 7.5-fold, at concentrations eliciting maximal induction, respectively. 2,3,7,8-tetrachlorodibenzo- p-dioxin, used as a positive control at a final concentration of 1.5 nM, caused a 30-fold increase in EROD activity. The induction of EROD activity was accompanied by an increase in CYP1A1 and CYP1A2 mRNA expression levels. Niclosamide, 4-chlorophenylbiguanide, dapsone, amodiaquine and desethylamodiaquine caused slight increases in EROD activity. No effect on CYP1A was observed for artemisinin, suramin, diethylcarbamazine, pyrimethamine, metrifonate, ivermectin, pyrantel artesunate, cycloguanil, atovaquone, melarsoprol, praziquantel, proguanil and dihydroartemisinin.
Quinine, albendazole and primaquine induce CYP1A1 and CYP1A2 at the transcriptional level. Considering the plasma concentrations (C(max)) achieved in vivo after administration of a therapeutic dose, induction by quinine and albendazole might be of clinical significance. The induction by primaquine, however, may not be of pharmacological or toxicological significance as concentrations at which it occurs are much higher than those attained in vivo.