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1.
Chem Biol Drug Des ; 95(5): 520-533, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32060993

RESUMO

Enzymes in the cytochrome P450 family 1 (CYP1) catalyze metabolic activation of procarcinogens and deactivation of certain anticancer drugs. Inhibition of these enzymes is a potential approach for cancer chemoprevention and treatment of CYP1-mediated drug resistance. We characterized inhibition of human CYP1A1, CYP1A2, and CYP1B1 enzymes by the novel inhibitor N-(3,5-dichlorophenyl)cyclopropanecarboxamide (DCPCC) and α-naphthoflavone (ANF). Depending on substrate, IC50 values of DCPCC for CYP1A1 or CYP1B1 were 10-95 times higher than for CYP1A2. IC50 of DCPCC for CYP1A2 was 100-fold lower than for enzymes in CYP2 and CYP3 families. DCPCC IC50 values were 10-680 times higher than the ones of ANF. DCPCC was a mixed-type inhibitor of CYP1A2. ANF was a competitive tight-binding inhibitor of CYP1A1, CYP1A2, and CYP1B1. CYP1A1 oxidized DCPCC more rapidly than CYP1A2 or CYP1B1 to the same metabolite. Molecular dynamics simulations and binding free energy calculations explained the differences of binding of DCPCC and ANF to the active sites of all three CYP1 enzymes. We conclude that DCPCC is a more selective inhibitor for CYP1A2 than ANF. DCPCC is a candidate structure to modulate CYP1A2-mediated metabolism of procarcinogens and anticancer drugs.


Assuntos
Amidas/química , Benzoflavonas/química , Ciclopropanos/química , Inibidores das Enzimas do Citocromo P-450/química , Família 1 do Citocromo P450/antagonistas & inibidores , Amidas/metabolismo , Benzoflavonas/metabolismo , Sítios de Ligação , Domínio Catalítico , Cumarínicos/química , Cumarínicos/metabolismo , Ciclopropanos/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/química , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1B1/antagonistas & inibidores , Citocromo P-450 CYP1B1/metabolismo , Inibidores das Enzimas do Citocromo P-450/metabolismo , Família 1 do Citocromo P450/metabolismo , Humanos , Fígado/enzimologia , Simulação de Dinâmica Molecular , Oxirredução
2.
Int J Cancer ; 115(6): 879-84, 2005 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15723309

RESUMO

Our study was designed to assess the fecal and urinary excretion of 3 aflatoxin B1 (AFB1) metabolites, aflatoxins M1 (AFM1) and Q1 (AFQ1) and aflatoxin B1-N7-guanine (AFB-N7-guanine) that are produced by the predominant forms of cytochrome P450 enzymes responsible for the biotransformation of AFB1. Fecal and urinary AFM1, AFQ1 and urinary AFB-N7-guanine were assessed in 83 young Chinese males selected from a larger population (n = 300) based on detectable urinary AFM1. The concentration of fecal AFQ1 (median 137 ng/g fresh weight, IQR 9.1 to 450) was approximately 60 times higher than that of AFM1 (2.3 ng/g, IQR 0.0 to 7.3). In urine, the median AFQ1 was 10.4 ng/ml (IQR 3.4 to 23.3), and the median AFM1 and AFB-N7-guanine 0.04 ng/ml (IQR 0.01 to 0.33) and 0.38 ng/ml (IQR 0.0 to 2.15), respectively. A subgroup (n = 14) with hepatitis B virus (HBV) infection had significantly higher fecal concentrations of AFQ1 (p = 0.043) and AFM1 (p = 0.001) than those who were hepatitis B-virus antigen (HBsAg) negative, and the respective differences in urinary AFQ1 and AFM1 concentrations approached statistical significance (p = 0.054, p = 0.138). Our study demonstrates that AFQ1 is excreted in urine and feces at higher levels than AFM1, and feces are an important route of excretion of these AFB1 metabolites. AFQ1 should be further assessed for its predictive value as a marker for exposure and risk of dietary aflatoxins.


Assuntos
Aflatoxina B1/análogos & derivados , Aflatoxina B1/metabolismo , Aflatoxina B1/urina , Guanina/análogos & derivados , Aflatoxina M1/urina , Aflatoxinas/urina , China , Fezes/química , Guanina/urina , Hepatite B/complicações , Hepatite B/urina , Humanos , Masculino
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