title: Inhibition of human and rat CYP1A1 enzyme by grapefruit juice compounds.
abstract: Cytochrome P4501A1 is involved in the metabolism of carcinogenic polycyclic aromatic hydrocarbons; therefore, its inhibition interferes with the carcinogenesis process induced by these compounds in rats. The human and rat CYP1A1 differ by 21% in amino acid sequence, including the active site of the enzyme; this difference may be an important factor when results obtained using animal models are interpolated to humans. Based on its previously reported CYP inhibitory properties, we studied the effects of two molecules contained within grapefruit juice, naringenin and 6',7'-dihydroxybergamottin, on human and rat CYP1A1 activity. For this purpose, the kinetics of inhibition as well as computational simulations were used. Naringenin and 6',7'-dihydroxybergamottin were found to be competitive inhibitors of human and rat CYP1A1. Additionally, naringenin exerted a mixed type inhibition effect on rat CYP1A1. Computational docking showed that inhibitors might block the oxidation of 7-ethoxyresorufin by binding to the CYP1A1 active site. Our results demonstrate the differences in CYP inhibitory mechanisms for the same molecule when CYP from different species are considered.
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Cd. de México, México.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Santes-Palacios
authors.affiliation: División de Estudios de Posgrado, Facultad de Química, Universidad Autónoma de Querétaro, Santiago de Querétaro, México.
authors.forename: Antonio
authors.initials: A
authors.lastname: Romo-Mancillas
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Cd. de México, México.
authors.forename: Rafael
authors.initials: R
authors.lastname: Camacho-Carranza
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Cd. de México, México. Electronic address: jjea99@gmail.com.
authors.forename: Jesús Javier
authors.initials: JJ
authors.lastname: Espinosa-Aguirre
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D020134:Catalytic Domain; D032083:Citrus paradisi / Q000737:chemistry*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044950:Flavanones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018565:Food-Drug Interactions; D000067030:Fruit and Vegetable Juices / Q000032:analysis*; D011564:Furocoumarins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D044950:Flavanones; D011564:Furocoumarins; D008024:Ligands; D011994:Recombinant Proteins; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C005273:naringenin; C104774:6',7'-dihydroxybergamottin
keywords: CYP1A1 inhibitor; Dihydroxybergamottin; Molecular modeling; Naringenin