title: Effects of green tea compounds on irinotecan metabolism.
abstract: The effects of green tea compounds on the metabolism of irinotecan have never been investigated. We aimed to study whether catechins [(-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), (-)-epicatechin] affect the inactivation metabolism of irinotecan into 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecin (NPC) (by CYP3A4) and 7-ethyl-10-hydroxycamptothecin (SN-38) into 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) (by UGT1A1). Human liver microsomes, hepatocytes and Hep G2 cells were incubated with catechins and treated with irinotecan and/or SN-38. NPC and SN-38G formation was measured by high-performance liquid chromatography. UGT1A1 mRNA levels were measured by real-time polymerase chain reaction. In human liver microsomes, a concentration-dependent decrease in the formation of NPC and SN-38G was observed. In human hepatocytes, a significant increase in SN-38G production was observed in 33% (EGCG), 44% (ECG), and 44% (EGC) of the hepatocyte preparations. Phenobarbital increased the formation of SN-38G in 100% of the same hepatocyte preparations. In Hep G2 cells, no increase in SN-38G formation was observed. With the exception of ECG in one liver, catechins did not increase UGT1A1 mRNA levels. NPC production was also significantly increased in 40% of the hepatocyte preparations for each catechin. However, the production of 6beta-hydroxytestosterone remained unaffected in other hepatocyte preparations. At pharmacologically relevant concentrations, catechins are unlikely to inhibit the formation of irinotecan inactive metabolites when administered concomitantly. The induction effect of catechins on UGT1A1 seems to be modest and highly variable. Catechins do not induce CYP3A4 activity. The effect of acute and prolonged use of green tea on the pharmacokinetics of irinotecan in patients remains to be evaluated.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Komoroski
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Andrea Yoder
authors.initials: AY
authors.lastname: Graber
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006915:Hydroxytestosterones; D000077146:Irinotecan; D012333:RNA, Messenger / Q000032:analysis; D013662:Tea; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D002392:Catechin; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D005965:Glucuronates; D014453:Glucuronosyltransferase; D006915:Hydroxytestosterones; D000077146:Irinotecan; D012333:RNA, Messenger; D013662:Tea; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; C025591:6 beta-hydroxytestosterone; C062669:epicatechin gallate; C045651:epigallocatechin gallate; C510163:CYP3A4 protein, human; C057580:gallocatechol