Oxidations of 17 beta-estradiol and estrone and their interconversions catalyzed by liver, mammary gland and mammary tumor after acute and chronic treatment of rats with indole-3-carbinol or beta-naphthoflavone

Altered cytochrome P450-catalyzed metabolism of 17 beta -estradiol (E2) and estrone (E1) in the liver and (or) extrahepatic tissues may affect estroge n-sensitive tumorigenesis. We examined the effects of oral treatments of (i ) indole-3-carbinol (I3C) at 250 or 500 mg/kg or beta -naphthoflavone (beta -NF) at 40 mg/kg of body weight (bw)/day from 51 to 54 days of age (acute regimen), and (ii) I3C at 250 mg/kg or beta -NF at 20 mg/kg bw given 3x/wee k from 10 to 22 weeks of age (chronic regimen) in female Sprague-Dawley rat s. We determined the effects of these treatments on the P450 content and P4 50 (CYP)-specific activities in the liver, P450-dependent metabolism of E2 and E1 by the liver and mammary gland, and interconversion of E1 and E2 cat alyzed by 17 beta -hydroxysteroid dehydrogenase (17 beta -HSD) in these tis sues and malignant mammary tumors. I3C at the two levels of acute regimen e licited similar responses. Acute and chronic treatments with I3C, but not b eta -NF, increased P450 content similar to2-fold. I3C, and to a lesser exte nt beta -NF, increased CYP1A1 and CYP1A2 probe activities in liver up to 11 7- and 27- fold, respectively, and after acute regimens, that of CYP3A by s imilar to1.8-fold. I3C also increased activity of CYP2B up to 100-fold. Ove rall hepatic metabolism of E2 and E1, which was similar to2-fold greater at 55 than 155 days of age, was increased (similar to2.8-fold) by I3C with 2- , 4-, 16 alpha-, 6 alpha-, 6 beta-, and 15 alpha -hydroxy (OH) comprising g reater than or equal to 54, 3, 2, similar to2, similar to5, 7, and 2%, resp ectively, of E1 and E2 metabolites. Acute regimens of beta -NF increased 2- and 15 alpha -OH-E2 (62 and 5% of total) from E2 and 2-, 4-, and 6 alpha - OH-E1 + 6 beta -OH-E1 (32, 13, and 4% of total) from E1. Mammary gland meta bolized E2 to E1 and small amounts of 15 alpha-, 4-, 16 alpha-, 6 beta-, an d 6 alpha -OH-E2. After the acute IC3 regimen, E2 was also converted to 2-O H-E2. 17 beta -HSD-catalyzed oxidation of E2 was favored in the liver and r eduction of E1 was favored in mammary gland and tumor (= 1% of hepatic acti vity). An increased (similar to2-fold) ratio of reductive to oxidative acti vities in malignant mammary tumors by chronic I3C regimen may stimulate tum or growth. This is the first report showing that after chronic oral regimen s, the I3C-, but not beta -NF-, induced changes in CYP complement led to el evated E2 and E1 metabolism. The persistent effects of increased putative c arcinogenic and estrogenic 4- and 16 alpha -OH as well as 6 alpha- and 6 be ta -OH-E2 and 6 beta -OH-E1 might counteract those of the less estrogenic 2 -OH metabolites, thus accounting for the lack of suppression of mammary tum origenesis by I3C in our previous study.