Biotransformation of glucoaurantio-obtusin towards aurantio-obtusin increases the toxicity of irinotecan through increased inhibition towards SN-38 glucuronidation.
The present study aims to investigate the influence of irinotecan's toxicity by the biotransformation of glucoaurantio-obtusin to aurantio-obtusin. Intraperitoneal administration (i.p.) of 100 mg/kg aurantio-obtusin significantly increased the toxicity of irinotecan, but the i.p. administration of 100 mg/kg glucoaurantio-obtusin showed negligible influence towards irinotecan's toxicity. Furthermore, the mechanism was explained through determining the inhibition potential of glucoaurantio-obtusin and aurantio-obtusin towards the glucuronidation metabolism of SN-38 that has been regarded to be the major active product responsible for the toxicity of irinotecan. The results showed that aurantio-obtusin exhibited strong competitive inhibition towards the glucuronidation of SN-38, but negligible inhibition potential of glucoaurantio-obtusin towards SN-38 glucuronidation was observed. These results showed that biotransformation of glucoaurantio-obtusin towards aurantio-obtusin increased the toxicity of irinotecan through increased inhibition of SN-38 glucuronidation.
First Affiliated Hospital of Dalian Medical University, Dalian, China.
Jian
J
Yu
Jing-Chun
JC
Han
Ya-Jie
YJ
Gao
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D000077146:Irinotecan; D008297:Male; D057507:Mice, 129 Strain
D000880:Anthraquinones; D000972:Antineoplastic Agents, Phytogenic; C000595611:aurantio-obtusin; D000077146:Irinotecan; D002166:Camptothecin
SN-38; herb-drug interaction; irinotecan; toxicity