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1.
J Agric Food Chem ; 72(15): 8618-8631, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38569082

RESUMO

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.


Assuntos
Isoflavonas , Pró-Fármacos , Animais , Ratos , Administração Oral , Aminoácidos/química , Disponibilidade Biológica , Carbamatos/química , Pró-Fármacos/química , Solubilidade , Água
2.
Chem Res Toxicol ; 29(3): 359-66, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26886724

RESUMO

8-Epidiosbulbin E acetate (EEA), a furanoid, was unexpectedly found to be the most abundant diterpenoid lactone in certain varieties of Dioscorea bulbifera L. (DB), a traditional herbal medicine widely used in Asian nations. This herb has been reported to cause liver injury in humans and experimental animals. The occurrence of EEA in DB was dependent on its commercial source. The present study shows that EEA exhibits time- and dose-dependent liver injury in mice. Pretreatment with ketoconazole prevented the animals from developing EEA-induced liver injury, caused 7- and 13-fold increases in the plasma Cmax and AUC of EEA, and decreased urinary excretion of glutathione conjugates derived from EEA. Pretreatment with buthionine sulfoximine exacerbated EEA-induced hepatotoxicity. In order to define the role of EEA's furan moiety in EEA-induced hepatotoxicity, we synthesized tetrahydro-EEA by catalytic hydrogenation of the furan moiety. No liver injury was observed in the animals given the same doses of tetrahydro-EEA as those used with EAA. The results indicate that EEA itself does not appear to be hepatotoxic but that the electrophilic intermediate generated by the metabolic activation of the furan ring mediated by cytochromes P450 is responsible for EEA-induced liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Diterpenos/metabolismo , Diterpenos/toxicidade , Ativação Metabólica/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/administração & dosagem , Relação Dose-Resposta a Droga , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Fatores de Tempo
3.
Arch Toxicol ; 90(4): 863-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25851819

RESUMO

Diosbulbin B (DIOB), a furanoid, is a major constituent of herbal medicine Dioscorea bulbifera L. Exposure to DIOB caused liver injury in humans and experimental animals. The mechanisms of DIOB-induced hepatotoxicities remain unknown. The present study demonstrated that DIOB induced hepatotoxicities in a time- and dose-dependent manner in mice. H&E stained histopathologic image showed the occurrence of necrosis in the liver obtained from the mice treated with DIOB at dose of 200 mg/kg. Pretreatment with KTC protected the animals from hepatotoxicities and hepatic GSH depletion induced by DIOB, increased area under the concentration-time curve of blood DIOB, decreased urinary excretion of GSH conjugates derived from DIOB, and increased urinary excretion of parent drug. Pretreatment with BSO exacerbated DIOB-induced hepatotoxicities. In order to define the role of furan moiety in DIOB-induced liver toxicities, we replaced the furan of DIOB with a tetrahydrofuran group by chemical hydrogenation of the furan ring of DIOB. No liver injury was observed in the animals given the same doses of tetrahydro-DIOB. The furan moiety was essential for DIOB-induced hepatotoxicities. The results implicate the cis-enedial reactive metabolite of DIOB was responsible for the observed toxicities. The observed modest depletion of hepatic GSH in DIOB-treated animals suggests the actions of one or more reactive metabolites, and the hepatic injury observed could be due at least in part to reactions of these metabolites with crucial biomolecules. Cytochrome P450 3A enzymes are implicated in DIOB-induced hepatotoxicities by catalyzing the formation of the reactive metabolite of DIOB.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Fígado/efeitos dos fármacos , Ativação Metabólica , Animais , Butionina Sulfoximina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Furanos/química , Furanos/toxicidade , Glutationa/metabolismo , Glutationa/urina , Compostos Heterocíclicos de 4 ou mais Anéis/química , Cetoconazol/farmacologia , Fígado/metabolismo , Masculino , Camundongos , Relação Estrutura-Atividade
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