Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss-Webster mouse.
This study was designed to determine the effect of the in vivo administration of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) on enzymes involved in the synthesis and metabolism of estradiol. EGCG (12.5, 25, or 50 mg/kg/day, i.p.) or ECG (12.5 or 25 mg/kg/day, i.p.) was administered to female Swiss-Webster mice for 7 days. The chemicals were well tolerated by the mice with the exception of EGCG given at 50 mg/kg, which resulted in severe hepatic necrosis and a 67% mortality rate. Following the administration of nontoxic doses of EGCG and ECG, aromatase (CYP19), CYP3A, CYP1A, and catechol O-methyltransferase (COMT) were measured. Additionally, the activity of CYP2E1 was determined, since this CYP450 isoform is important in the bioactivation of numerous carcinogens. The results demonstrated that ovarian aromatase activity was inhibited 56% by EGCG (25 and 12.5 mg/kg), but not ECG, while hepatic CYP3A catalytic activity and polypeptide levels were increased 31 +/- 4 and 47 +/- 2%, respectively, by 25 mg/kg of EGCG. However, ECG (but not EGCG) inhibited CYP1A catalytic activity and polypeptide levels (31 +/- 5 and 47 +/- 5%, respectively). Hepatic and renal COMT, as well as renal CYP3A remained unchanged following catechin dosing. Hepatic CYP2E1 catalytic activity and polypeptide levels were significantly increased (37 +/- 3 and 22 +/- 3%) following administration of EGCG (25 mg/kg). These results indicate that EGCG modulates enzymes responsible for both the synthesis and metabolism of estradiol, which may provide a potential mechanism for the reported action of EGCG, reported action as an inhibitor of breast tumor growth.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
Mette G
MG
Goodin
Rhonda J
RJ
Rosengren
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D051379:Mice; D009336:Necrosis; D010053:Ovary / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020033:Protein Isoforms
D000972:Antineoplastic Agents, Phytogenic; D020033:Protein Isoforms; D002392:Catechin; D003577:Cytochrome P-450 Enzyme System; C062669:epicatechin gallate; C045651:epigallocatechin gallate; D002394:Catechol O-Methyltransferase