Curcumin modulates drug metabolizing enzymes in the female Swiss Webster mouse.

Curcumin, the yellow pigment found in turmeric, exhibits potent chemopreventative properties in both in vivo and in vitro cancer models. We hypothesized that this effect may occur via curcumin-mediated changes in enzymes involved in both carcinogen bioactivation and estrogen metabolism. Female Swiss Webster mice were treated with either curcumin (200 mg/kg or 400 mg/kg, p.o.) or vehicle control for 1 or 2 weeks. The results demonstrated that curcumin had no effect on the catalytic activities of ovarian aromatase, hepatic catechol-O-methyltransferase or hepatic UDP-glucuronosyltransferase. However, both doses of curcumin caused a 25% decrease in CYP1A catalytic activity, but not polypeptide levels, following 2 weeks of treatment. Additionally, following 2 weeks of curcumin at 400 mg/kg, there was a 20% decrease in the catalytic activity and a 28% decrease in polypeptide levels of CYP3A. While 2 weeks of curcumin treatment (400 mg/kg) caused a 20% increase in glutathione S-transferase activity, there was no parallel increase in hepatic stores of the co-factor glutathione. In conclusion small changes in CYP1A, CYP3A and GST following long term treatment (2 weeks) suggest that the combination of all three metabolic pathways may play a small role in curcumin's chemopreventative action.

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.

Renal PGE2 production in the human and rat following phenacetin, acetaminophen and p-aminophenol.

Co-oxidation of phenacetin, acetaminophen (APAP) and p-aminophenol (p-AP) by prostaglandin H synthase (PHS) was investigated in human and rat renal microsomes. The formation of prostaglandin E2 (PGE2) was assessed in cortex, outer and inner medulla following phenacetin, APAP and p-AP (0-5 mM) incubations. For all compounds and concentrations tested, a significantly higher PGE2 production was observed in inner medulla compared to cortex. Rat inner medulla incubated with phenacetin resulted in an increased formation of PGE2 at all concentrations compared to control (1 mM phenacetin increased production by 243%). Human inner medulla demonstrated an increased PGE2 production at 1, 3 and 5 mM phenacetin versus control (136% increase at 1 mM). An increase in PGE2 formation in rat and human inner medulla was observed at low APAP concentrations (0.1, 0.3, 0.5 and 1 mM) compared to control (216% and 396% in human and rat respectively following 1 mM APAP). 5 mM APAP inhibited PGE2 formation in the rat inner medulla but not in human inner medulla. An inhibition of PGE2 production by 5 mM p-AP was observed in both the rat and human inner medulla. In the rat PGE2 production was inhibited 69% by 5 mM, whereas in the human the inhibition was 76% at 5 mM. These studies demonstrate a species-specific PHS-mediated renal metabolism of APAP, with the human kidney demonstrating a continous formation of reactive metabolites at high concentrations of APAP. However, phenacetin and p-AP are metabolized in a similar manner in these 2 species.