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Larsen-Su SA, Williams DE. Department of Environmental and Molecular Toxicology, 571 Weniger Hall, Oregon State University, Corvallis, OR 97331-6512, USA. Toxicol Sci. 2001 Dec;64(2):162-8. Indole-3-carbinol (I3C), a naturally occurring component of broccoli, cabbage, and other members of the family Cruciferae, is a tumor modulator in several animal models that demonstrates significant chemoprevention against development of both spontaneous and chemically induced cancers while conversely eliciting tumor promoter effects in others. This study examines the disposition of I3C in the pregnant rat model, specifically to determine whether I3C can traverse the maternal placenta, and what effects, if any, are elicited in the neonate. We now report that dietary I3C treatment of pregnant female rats results in appearance of I3C acid condensation products in both maternal and neonatal livers. Livers from I3C-fed maternal rats showed CYP1A1 protein induction; however, no CYP1B1 protein was detected. No CYP1A1 or CYP1B1 protein was detected in the livers of pregnant controls or their offspring. We also report a sex-specific induction of CYP1A1 and CYP1B1 protein in livers from newborns born to I3C-fed dams. CYP1A1 protein was significantly induced in male neonatal liver, but not in females. Conversely, hepatic CYP1B1 protein was induced to high levels in female neonates, with no CYP1B1 protein detected in male littermates. Our results demonstrate that dietary I3C acid condensation products can cross the maternal placenta and differentially induce neonatal hepatic CYP1A1 and CYP1B1 in a sex-specific manner. The results highlight the potential of I3C to effect changes in the overall metabolic profile of xenobiotics to which the fetus is exposed transplacentally and indicate the possible involvement of sex-specific modulators in Ah receptor-mediated responses in this model.
Ritter CL, Prigge WF, Reichert MA, Malejka-Giganti D. Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. Can J Physiol Pharmacol. 2001 Jun;79(6):519-32. Altered cytochrome P450-catalyzed metabolism of 17beta-estradiol (E2)
and estrone (E1) in the liver and (or) extrahepatic tissues may affect
estrogen-sensitive tumorigenesis. We examined the effects of oral treatments
of (i) indole-3-carbinol (13C) 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) 13C at 250 mg/kg or beta-NF at 20 mg/kg bw given
3x/week from 10 to 22 weeks of age (chronic regimen) in female Sprague-Dawley
rats. We determined the effects of these treatments on the P450 content
and P450 (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 catalyzed by 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in
these tissues and malignant mammary tumors. 13C at the two levels of acute
regimen elicited similar responses. Acute and chronic treatments with
13C, but not beta-NF, increased P450 content approximately 2-fold. 13C,
and to a lesser extent beta-NF, increased CYP1A1 and CYP1A2 probe activities
in liver up to 117- and 27- fold, respectively, and after acute regimens,
that of CYP3A by approximately 1.8-fold. 13C also increased activity of
CYP2B up to 100-fold. Overall hepatic metabolism of E2 and E1, which was
approximately 2-fold greater at 55 than 155 days of age, was increased
(approximately 2.8-fold) by 13C with 2-, 4-, 16alpha-, 6alpha-, 6beta-,
and 15alpha-hydroxy (OH) comprising > or = 54, 3, 2, approximately
2, approximately 5, 7, and 2%, respectively, of E1 and E2 metabolites.
Acute regimens of beta-NF increased 2- and 15alpha-OH-E2 (62 and 5% of
total) from E2 and 2-, 4-, and 6alpha-OH-E1 + 6beta-OH-E1 (32, 13, and
4% of total) from E1. Mammary gland metabolized E2 to E1 and small amounts
of 15alpha-, 4-, 16alpha-, 6beta-, and 6alpha-OH-E2. After the acute IC3
regimen, E2 was also converted to 2-OH-E2. 17Beta-HSD-catalyzed oxidation
of E2 was favored in the liver and reduction of E1 was favored in mammary
gland and tumor (= 1% of hepatic activity). An increased (approximately
2-fold) ratio of reductive to oxidative activities in malignant mammary
tumors by chronic 13C regimen may stimulate tumor growth. This is the
first report showing that after chronic oral regimens, the 13C-, but not
beta-NF-, induced changes in CYP complement led to elevated E2 and E1
metabolism. The persistent effects of increased putative carcinogenic
and estrogenic 4- and 16alpha-OH as well as 6alpha- and 6beta-OH-E2 and
6beta-OH-E1 might counteract those of the less estrogenic 2-OH metabolites,
thus accounting for the lack of suppression of mammary tumorigenesis by
13C in our previous study.
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