Distinct forms of hepatic androgen 6β-hydroxylase induced in the rat by indole-3-carbinol and pregnenolone carbonitrile

Jellinck, Peter H.; Newcombe, Anne-Marie; Forkert, Poh‐Gek; Martucci, Charles

doi:10.1016/0960-0760(94)90096-5

Cited by 12 publications

(3 citation statements)

References 32 publications

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“…The E p vs. pH plot for the oxidation peak I a was linear (Fig. 2) and the dependence of E p on pH using linear regression analysis can be expressed by relation (1) with a correlation coefficient ~0.99. The peak potential of the reduction peak II c was also dependent on pH and shifted to more negative potentials with an increase in pH.…”

Section: Electrochemical Oxidationmentioning

confidence: 87%

Oxidation chemistry of indole-3-methanol

Goyal

Kumar

Gupta

2001

J. Chem. Soc., Perkin Trans. 2

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The electrochemically driven and persulfate-mediated oxidations of indole-3-methanol have been studied in phosphate buffers. The electrochemical oxidation was carried out at a pyrolytic graphite electrode and the electrode reaction is found to follow the ECE mechanism. The kinetics of the UV-absorbing intermediate were followed spectrophotometrically and decay occurred in a pseudo-first-order reaction. On the other hand, the oxidation of indole-3-methanol by persulfate followed pseudo-first-order kinetics having first-order with respect to substrate. This reaction takes place with a second-order rate constant of (0.13 ± 0.005) dm 3 mol Ϫ1 s Ϫ1 . A detailed interpretation of the redox mechanism for indole-3-methanol in both the oxidations has been suggested.

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Section: Electrochemical Oxidationmentioning

confidence: 87%

Oxidation chemistry of indole-3-methanol

Goyal

Kumar

Gupta

2001

J. Chem. Soc., Perkin Trans. 2

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“…Activation of AhR by I3C in vivo depends on the formation of its condensation products in stomach acid (Bjeldanes et al 1991). In addition to CYP1A1 and CYP1A2, orally administered I3C induces CYP2B1/2 and CYP3A1 in the liver of female rats, indicating that it is a TCDD-and PB-or a mixed-type inducer (Jellinck et al 1993(Jellinck et al , 1994Grubbs et al 1995). Chronic oral administration of I3C (at 100 mg/day for 100 days) to female SD rats induced CYP1A1, CYP1A2, and CYP2B1 mRNAs and the respective CYP-specific EROD, MROD, and BROD activities, as well as CYP3A1 mRNA (Grubbs et al 1995).…”

Section: Discussionmentioning

confidence: 99%

“…β-NF is a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-type inducer that binds to the aryl hydrocarbon receptor (AhR) resulting in increased expression of mRNAs for several Phase I (oxidases, e.g., CYP1A1 and CYP1A2) and Phase II (conjugases) enzymes (Safe 1995). Because I3C, via its acid-catalyzed self-condensation products, induces CYP1A1 and CYP1A2 as well as the phenobarbital (PB)-inducible CYP2B and CYP3A it is considered a mixed-type inducer (Jellinck et al 1993(Jellinck et al , 1994Grubbs et al 1995). Thus, I3C and β-NF inhibit carcinogenesis at the initiation phase through increased carcinogen detoxification leading to decreased levels of carcinogen-derived DNA adducts critical for mutations and cell transformation in target tissues (Stresser et al 1994a(Stresser et al , 1994bVerhoeven et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Oxidations of 17β-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 β-naphthoflavone

Ritter¹,

Prigge²,

Reichert³

et al. 2001

Can. J. Physiol. Pharmacol.

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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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