Yongjie Zhang1, Nico P E Vermeulen1, Jan N M Commandeur1. 1. Division of Molecular Toxicology, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands.
Abstract
AIMS: Oxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N-desethylamodiaquine (DEAQ) is up to 240-fold higher than AQ, bioactivation of DEAQ might significantly contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes (HLM) and to characterize the CYPs involved in bioactivation of AQ and DEAQ. METHODS: Glutathione was used to trap reactive metabolites formed in incubations of AQ and DEAQ with HLM and recombinant human cytochrome P450s (hCYPs). Kinetics of bioactivation of AQ and DEAQ in HLM and involvement of hCYPs were characterized by measuring corresponding glutathione conjugates (AQ-SG and DEAQ-SG) using a high-performance liquid chromatography method. RESULTS: Bioactivation of AQ and DEAQ in HLM both exhibited Michaelis-Menten kinetics. For AQ bioactivation, enzyme kinetical parameters were Km , 11.5 ± 2.0 μmol l-1 , Vmax , 59.2 ± 3.2 pmol min-1 mg-1 and CLint , 5.15 μl min-1 mg-1 . For DEAQ, parameters for bioactivation were Km , 6.1 ± 1.3 μmol l-1 , Vmax , 5.5 ± 0.4 pmol min-1 mg-1 and CLint 0.90 μl min-1 mg-1 . Recombinant hCYPs and inhibition studies with HLM showed involvement of CYP3A4, CYP2C8, CYP2C9 and CYP2D6 in bioactivation. CONCLUSIONS: The major metabolite DEAQ is likely to be quantitatively more important than AQ with respect to hepatic exposure to reactive metabolites in vivo. High expression of CYP3A4, CYP2C8, CYP2C9, and CYP2D6 may be risk factors for hepatotoxicity caused by AQ-therapy.
AIMS: Oxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N-desethylamodiaquine (DEAQ) is up to 240-fold higher than AQ, bioactivation of DEAQ might significantly contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes (HLM) and to characterize the CYPs involved in bioactivation of AQ and DEAQ. METHODS:Glutathione was used to trap reactive metabolites formed in incubations of AQ and DEAQ with HLM and recombinant human cytochrome P450s (hCYPs). Kinetics of bioactivation of AQ and DEAQ in HLM and involvement of hCYPs were characterized by measuring corresponding glutathione conjugates (AQ-SG and DEAQ-SG) using a high-performance liquid chromatography method. RESULTS: Bioactivation of AQ and DEAQ in HLM both exhibited Michaelis-Menten kinetics. For AQ bioactivation, enzyme kinetical parameters were Km , 11.5 ± 2.0 μmol l-1 , Vmax , 59.2 ± 3.2 pmol min-1 mg-1 and CLint , 5.15 μl min-1 mg-1 . For DEAQ, parameters for bioactivation were Km , 6.1 ± 1.3 μmol l-1 , Vmax , 5.5 ± 0.4 pmol min-1 mg-1 and CLint 0.90 μl min-1 mg-1 . Recombinant hCYPs and inhibition studies with HLM showed involvement of CYP3A4, CYP2C8, CYP2C9 and CYP2D6 in bioactivation. CONCLUSIONS: The major metabolite DEAQ is likely to be quantitatively more important than AQ with respect to hepatic exposure to reactive metabolites in vivo. High expression of CYP3A4, CYP2C8, CYP2C9, and CYP2D6 may be risk factors for hepatotoxicity caused by AQ-therapy.
Authors: Richard A Thompson; Emre M Isin; Yan Li; Lars Weidolf; Ken Page; Ian Wilson; Steve Swallow; Brian Middleton; Simone Stahl; Alison J Foster; Hugues Dolgos; Richard Weaver; J Gerry Kenna Journal: Chem Res Toxicol Date: 2012-05-31 Impact factor: 3.739
Authors: Kimberly K Scarsi; Fatai A Fehintola; Qing Ma; Francesca T Aweeka; Kristin M Darin; Gene D Morse; Ibrahim Temitope Akinola; Waheed A Adedeji; Niklas Lindegardh; Joel Tarning; Oladosu Ojengbede; Isaac F Adewole; Babafemi Taiwo; Robert L Murphy; Olusegun O Akinyinka; Sunil Parikh Journal: J Antimicrob Chemother Date: 2014-01-19 Impact factor: 5.790
Authors: Siamak Cyrus Khojasteh; Saileta Prabhu; Jane R Kenny; Jason S Halladay; Anthony Y H Lu Journal: Eur J Drug Metab Pharmacokinet Date: 2011-02-19 Impact factor: 2.441
Authors: Choon-Sheen Lai; N K Nair; A Muniandy; S M Mansor; P L Olliaro; V Navaratnam Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2008-12-25 Impact factor: 3.205
Authors: Shalenie P den Braver-Sewradj; Michiel W den Braver; Robin M Toorneman; Stephanie van Leeuwen; Yongjie Zhang; Stefan J Dekker; Nico P E Vermeulen; Jan N M Commandeur; J Chris Vos Journal: Chem Res Toxicol Date: 2018-01-11 Impact factor: 3.739
Authors: Giovanni Bocci; Steven B Bradfute; Chunyan Ye; Matthew J Garcia; Jyothi Parvathareddy; Walter Reichard; Surekha Surendranathan; Shruti Bansal; Cristian G Bologa; Douglas J Perkins; Colleen B Jonsson; Larry A Sklar; Tudor I Oprea Journal: ACS Pharmacol Transl Sci Date: 2020-10-14
Authors: Yongjie Zhang; Shalenie P den Braver-Sewradj; Michiel W den Braver; Steven Hiemstra; Nico P E Vermeulen; Bob van de Water; Jan N M Commandeur; J C Vos Journal: Front Pharmacol Date: 2018-04-18 Impact factor: 5.810
Authors: Mikhail Martchenko Shilman; Gloria Bartolo; Saleem Alameh; Johnny W Peterson; William S Lawrence; Jennifer E Peel; Satheesh K Sivasubramani; David W C Beasley; Christopher K Cote; Samandra T Demons; Stephanie A Halasahoris; Lynda L Miller; Christopher P Klimko; Jennifer L Shoe; David P Fetterer; Ryan McComb; Chi-Lee C Ho; Kenneth A Bradley; Stella Hartmann; Luisa W Cheng; Marina Chugunova; Chiu-Yen Kao; Jennifer K Tran; Aram Derbedrossian; Leeor Zilbermintz; Emiene Amali-Adekwu; Anastasia Levitin; Joel West Journal: ACS Infect Dis Date: 2021-07-04 Impact factor: 5.084