Microsomal metabolism of the carcinogen, N-2-fluorenylacetamide, by the mammary gland and liver of female rats. I. Ring- and N-hydroxylations of N-2-fluorenylacetamide

Malejka-Giganti, Danuta; Decker, Richard W.; Ritter, Clare L.; Polovina, Milo R.

doi:10.1093/carcin/6.1.95

Cited by 13 publications

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“…On the basis of O 2 uptake during NADH-dependent 9-oxo-2,4,7-triNF reduction catalyzed by mammary gland cytosol and microsomes (20) and on the basis of the inhibition by O 2 of amine formation from nitrofluorenes catalyzed by diaphorase and XO (19), the inhibition by O 2 herein (Table 4) is attributed to its interaction with nitro anion radical and other O 2 -sensitive intermediates. Microsomal nitroreduction may be linked to the NADPH cytochrome P450 and NADH cytochrome c reductases found in rat mammary gland (33). Although microsomal nitroreduction of 9-oxo-2-NF seems to prefer NADH, it may be underestimated with NADPH because of the rapid carbonyl reduction.…”

Section: Discussionmentioning

confidence: 98%

Reductions of Nitro and 9-Oxo Groups of Environmental Nitrofluorenes by the Rat Mammary Gland in Vitro

Ritter

Decker

Malejka-Giganti

2000

Chem. Res. Toxicol.

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Nitrofluorenes and C-9-oxidized nitrofluorenes are widespread environmental genotoxins which may be relevant for breast cancer on the basis of their carcinogenicities, particularly of 2, 7-dinitrofluorene (2,7-diNF), for the rat mammary gland. Since their metabolism to active carcinogens may involve nitroreduction, this study examined the reduction of 2-nitrofluorene (2-NF) and 2,7-diNF and their 9-oxo- and 9-hydroxy (OH) derivatives by the rat mammary gland. Cytosolic fractions catalyze NADH- and NADPH-dependent reductions of the 2-nitro and 9-oxo to the respective 2-amino and 9-OH compounds at rates 4- and >/=10-fold greater than those with microsomes. Rates of amine formation catalyzed by cytosol from 2, 7-diNF are greater than the rate from 2-NF and increase for C-9-oxidized derivatives: 9-oxo-2-NF > 9-OH-2-NF > 2-NF and 9-OH-2, 7-diNF >> 9-oxo-2,7-diNF > 2,7-diNF. Nitroreduction is inhibited by O(2) or allopurinol (20 microM), dicoumarol (100 microM), and rutin (50 microM). 9-Oxoreduction is inhibited by rutin, dicoumarol, and indomethacin (100 microM), but not by O(2) or allopurinol. Pyrazole or menadione does not inhibit nitro or 9-oxoreduction. Xanthine, hypoxanthine, 2-hydroxypyrimidine, and N'-methylnicotinamide support cytosol-catalyzed nitro, but not 9-oxo, reduction. The data suggest that the nitroreduction is catalyzed largely by a xanthine oxidase and partially by a diaphorase and 9-oxoreduction by a carbonyl reductase. The extents of the nitro and carbonyl reductions of the nitrofluorenes may determine their reactivities with DNA, and thus genotoxicities for the mammary gland.

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Section: Discussionmentioning

confidence: 98%

Reductions of Nitro and 9-Oxo Groups of Environmental Nitrofluorenes by the Rat Mammary Gland in Vitro

Ritter

Decker

Malejka-Giganti

2000

Chem. Res. Toxicol.

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“…2). However, the same dose of β-NF (40 mg/kg bw) given as three intraperitoneal (ip) injections increased the P450 content of hepatic microsomes ≥1.6-fold in female rats (Malejka-Giganti et al 1985, 1989. The data suggest that the complement of the induced and (or) constitutive CYP(s) varies after oral versus ip treatment with β-NF; this might be due to differences in its metabolism.…”

Section: Discussionmentioning

confidence: 87%

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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“…On the days shown in Figure 1, rats from each group were killed by decapitation under CO2, and livers were removed. After washing with icecold saline, livers were homogenized in 4 volumes of 50 mM Tris-HCl 154 mM KCl buffer, pH 7.4, as described previously (14). Whole homogenates and the cytosolic fractions (105,000g supernatants) were used for enzyme assays.…”

Section: Treatment Ofrats and Preparation Oflivermentioning

confidence: 99%

Modulations of Hepatic g-Glutamyltranspeptidase and N-Hydroxy-N-2-Fluorenylacetamide Sulfotransferase Activities Following Treatment of Rats with a Hepatocarcinogenic Regimen: Effect of Partial Hepatectomy

Vijayaraghavan¹,

Malejka-Giganti²

1994

Environmental Health Perspectives

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The feasibility of using biochemical assays of gamma-glutamyltranspeptidase (gamma-GTP) and N-hydroxy-N-2-fluorenylacetamide sulfotransferase (N-OH-2-FAA ST) activities to monitor the effects of treatment of male Sprague-Dawley rats with a two-stage hepatocarcinogenic regimen was investigated. One week after initiation with diethylnitrosamine (200 mg/kg of bw), the rats were treated with 10 oral doses within 2 weeks of N-2-fluorenylacetamide (2-FAA) at 0.05 mmole/kg or vehicle (corn oil) at 5 ml/kg of body weight. After five doses of 2-FAA or corn oil, half of the rats in each group underwent partial (70%) hepatectomy (PH). Three days after completion of 2-FAA treatment, gamma-GTP activity increased approximately 8-fold in the livers of both the nonhepatectomized (-PH) and hepatectomized (+PH) groups. After 17 days, the enzyme activity decreased to the control level in the -PH group but increased 3.1-fold above the control level in the +PH group. After 31, 66, and 87 days, gamma-GTP activity increased only 1.4- to 2.6-fold in the -PH group, whereas that of +PH group increased 15- to 32-fold. N-OH-2-FAA ST activity, determined 3 days after completion of 2-FAA treatment, decreased by approximately 60% in the -PH and +PH groups. After 17 days, the effect of PH became evident in that the losses of N-OH-2-FAA ST activity were smaller (20%) in the -PH than in the +PH group (45.5%). After 31, 66, and 87 days, the respective decreases of 27, 29, and 41% in the +PH group were significant.(ABSTRACT TRUNCATED AT 250 WORDS)

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Microsomal metabolism of the carcinogen, N-2-fluorenylacetamide, by the mammary gland and liver of female rats. I. Ring- and N-hydroxylations of N-2-fluorenylacetamide

Cited by 13 publications

References 0 publications

Reductions of Nitro and 9-Oxo Groups of Environmental Nitrofluorenes by the Rat Mammary Gland in Vitro

Reductions of Nitro and 9-Oxo Groups of Environmental Nitrofluorenes by the Rat Mammary Gland in Vitro

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

Modulations of Hepatic g-Glutamyltranspeptidase and N-Hydroxy-N-2-Fluorenylacetamide Sulfotransferase Activities Following Treatment of Rats with a Hepatocarcinogenic Regimen: Effect of Partial Hepatectomy

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