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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh001
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 4, 2003; accepted September 22, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

Epigallocatechin Gallate Modulates CYP450 Isoforms in the Female Swiss Webster Mouse

Mette G. Goodin 1 and Rhonda J. Rosengren 1*

1 Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand

* To whom correspondence should be addressed. E-mail: rhonda.rosengren{at}stonebow.otago.ac.nz.


  Abstract

This study was designed to determine the effect of the in vivo administration of EGCG and ECG on enzymes involved in the synthesis and metabolism of estradiol. EGCG (12.5, 25 or 50 mg/kg/day, ip) or ECG (12.5 or 25 mg/kg/day, ip) was administered to female Swiss Webster mice for 7 days. The chemicals were well tolerated by the mice with the exception of EGCG (50 mg/kg) which resulted in severe hepatic necrosis and a 67% mortality rate. Following the administration of non-toxic 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 EGCG's reported action as an inhibitor of breast tumor growth.

Key Words: epigallocatechin gallate, CYP19, CYP3A, CYP1A, catechol O-methyltransferase .


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