RESUMEN
We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.
Asunto(s)
Benzbromarona/análogos & derivados , Benzbromarona/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Uricosúricos/química , Uricosúricos/metabolismo , Activación Metabólica , Animales , Benzbromarona/farmacología , Benzbromarona/toxicidad , Técnicas de Química Sintética , Células HEK293 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Ratas , Ácido Úrico/metabolismo , Uricosúricos/farmacología , Uricosúricos/toxicidadRESUMEN
Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl)benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity.
Asunto(s)
Benzbromarona/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Activación Metabólica , Animales , Células Hep G2 , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Bisphenol A (BPA), an industrial chemical with estrogenic activity, was investigated as a substrate for the ipso-metabolism catalyzed by microsomal cytochrome P450 (P450). BPA was expected to be transformed to a quinol via an ipso-addition reaction; however, hydroquinone (HQ) was detected as a metabolite via an ipso-substitution reaction. Isopropenylphenol (IPP) and hydroxycumyl alcohol (HCA) were also produced as eliminated metabolites by C-C bond scission via ipso-substitution. Incorporation of the ¹8O atom to HCA from H2¹8O suggested the presence of a carbocation intermediate. Bulkiness of p-substituted group of BPA and/or stability of the eliminated carbocation intermediate may cause ipso-substitution of BPA. CYP3A4 and CYP3A5 showed higher activity for ipso-substitution. CYP2D6*1 also showed the activity; however, the other 9 isozymes did not. IPP showed ER-binding activity in the same degree of BPA. Furthermore, the ER-binding activity of HCA was about a hundred times greater than that of BPA. These results suggested that this new metabolic pathway contributes to the activation of the estrogenic activity of BPA.