RESUMEN
Using DNA comet assay we found that polysaccharides from Tussilago farfara L. reduced the intensity of polychemotherapy-induced apoptosis and DNA damage in bone marrow cells and small intestinal epithelium of C57Bl/6 mice, which attested to genoprotective properties of these polysaccharides.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/antagonistas & inhibidores , Células de la Médula Ósea/efectos de los fármacos , ADN/química , Mucosa Intestinal/efectos de los fármacos , Polisacáridos/farmacología , Tussilago/química , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Cisplatino/antagonistas & inhibidores , Cisplatino/toxicidad , Ensayo Cometa , ADN/metabolismo , Duodeno/citología , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Femenino , Inyecciones Intraperitoneales , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Irinotecán/antagonistas & inhibidores , Irinotecán/toxicidad , Ratones , Ratones Endogámicos C57BL , Paclitaxel/antagonistas & inhibidores , Paclitaxel/toxicidad , Extractos Vegetales/química , Polisacáridos/aislamiento & purificaciónRESUMEN
PURPOSE: The chemotherapeutic agent irinotecan is hydrolyzed to its active form SN-38 by human carboxyesterases, but SN-38 is converted into the inactive form SN-38G by hepatic UDP-glucuronosyltransferases (UGTs). The aim of the present study was to evaluate the inhibitory effects of two b-glucuronidase-treated Japanese traditional herbal medicines (kampo), Hange-Shashin-To (TJ-14) and Sairei-To (TJ-114) on SN-38 glucuronidation, and the deglycosylation of baicalin (BG) and glycyrrhizic acid (GL) derived from TJ-14 and TJ-114 to form their respective aglycones, baicalein (BA) and glycyrrhetinic acid (GA). METHODS: The inhibitory effects of b-glucuronidase-treated TJ-14 and TJ-114 on SN-38 glucuronidation by human liver microsomes were examined. BA and GA, which were enzymatically converted from BG and GL present in TJ-14 and TJ-114, were examined in the same manner. Furthermore, the enzymatic activities were measured by using recombinant UGT1A1 and UGT1A9 isoforms instead of human liver microsomes. BA, GA, SN-38, and their glycosides/glucuronides were analyzed with an LC-MS system. RESULTS: As regards the linear initial reaction rate, SN-38 glucuronidation by human liver microsomes was significantly inhibited by the addition of b-glucuronidase-untreated TJ-14 and TJ-114, but was more strongly inhibited by the addition of b-glucuronidase-treated TJ-14 and TJ-114. The results of LC-MS analysis and pharmacokinetic studies suggested that BA is the main inhibitor of SN-38 glucuronidation. In the Dixon plot, BA showed competitive inhibition of SN-38 glucuronidation, and the inhibition constant was 8.70 ± 3.24 mM. Previous reports, studies of recombinant UGT isoforms indicated that SN-38 glucuronidation was mainly catalyzed by UGT1A1. CONCLUSIONS: These findings strongly suggested that SN-38 glucuronidation is inhibited by BA. BA could act as a pharmacokinetic regulating factor associated with SN-38 glucuronidation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.