Cytochrome P-450 C-M/F, new constitutive form of microsomal cytochrome P-450 in male and female rat liver with estrogen 2- and 16.alpha.-hydroxylase activity

Sugita, Osamu; Sassa, Shigeru; Miyairi, Shinichi; Fishman, Jack; Kubota, Ichiro; Noguchi, Teruhisa; Kappas, Attallah

doi:10.1021/bi00402a028

Cited by 20 publications

(3 citation statements)

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“…Many different isoforms of cytochrome P450 contribute to the 2-hydroxylation of estradiol in the liver. In rats, hepatic 2-hydroxylation of estradiol is catalyzed by cytochromes P450 1A2, 2B1/2B2, 2C6, 2C11, C-M/F (one or more members of the 2D family) and the 3A family (108,111,(113)(114)(115)(116)(117). In humans, cytochrome P450 1A2 and the 3A family are major enzymes for hepatic estrogen 2hydroxylation (112,(118)(119)(120)(121).…”

Section: -Hydroxylationmentioning

confidence: 99%

“…In male and female rats, the constitutively expressed hepatic cytochrome P450 C-M/F (thought to be a member of the 2D family; see ref. 116) has high activity for the 2-and 16αhydroxylation of estradiol and weak activity for 6α-, 6β-and 15α-hydroxylation of estradiol and for the conversion of estradiol to estrone (114). Cytochrome P450 2C11, a male specific isoform in rats, also catalyzes estrogen 16αhydroxylation (115) and liver microsomes from male rats catalyze the 16α-hydroxylation of estradiol to a much greater extent than liver microsomes from female rats (46).…”

Section: α-Hydroxylationmentioning

confidence: 99%

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Functional role of estrogen metabolism in target cells: review and perspectives

1998

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Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.

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Section: -Hydroxylationmentioning

confidence: 99%

Section: α-Hydroxylationmentioning

confidence: 99%

Functional role of estrogen metabolism in target cells: review and perspectives

1998

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“…Other investigators have reported large amounts of E1 from E2 catalyzed by rat liver microsomes or purified CYPs (Sugita et al 1988;Watanabe et al 1991;Suchar et al 1995). 17β-HSD may also contribute to the interconversions of E1 and E2 by liver microsomes.…”

Section: Discussionmentioning

confidence: 94%

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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The rat cytochrome P450 C&hyphen;M/F (CYP2D) subfamily: Constitutive P450 isozymes in male and female

Ishida

Sugita

1994

Stem Cells

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Cytochrome P450 (CYP) isozymes have been cloned from various tissues and species and form the cytochrome P450 superfamily. We have isolated cytochrome P450 C‐M/F, which we regard as a major form of the constitutive cytochrome P450 isozyme. Cytochrome P450 C‐M/F was highly active in the 2‐ and 16α‐hydroxylation of estrogens, as well as in the N‐demethylation of ethyl‐morphine and benzphetamine. It was essentially uninducible by phenobarbital, 3‐methylcholan‐threne or β‐naphthoflavone. Immunochemical studies demonstrated the presence of cytochrome P450 C‐M/F in the liver of male and female rats and in the kidney of male rats. This is consistent with P450 C‐M/F activity towards estrogens, since they are metabolized in the liver and kidney and excreted into the urine. Highly similar genes were identified by immunoscreening, and comprised the CYP2D sub‐family. Five genes—CYP2D1, CYP2D2, CYP2D3, CYP2D4 and CYP2D5—have been isolated from rats. In spite of the high similarity, there is an obvious difference in substrate specificity between even the most similar isozymes. Among allelic variants reported for CYP2D1 and CYP2D2, P450IID1v is a mutant with decreased activity specifically towards bufuralol, due to a single amino acid substitution. Biochemical studies have demonstrated enzyme activities of CYP2D1 and CYP2D2 isozymes, while those of CYP2D3, CYP2D4 and CYP2D5 remain unknown. It is suggested that CYP2D isozymes play a role in maintaining homeostasis of the organism since they are constitutively expressed in the livers of both sexes and in the kidneys of males. Understanding their endogenous substrates should help to clarify their roles.

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Cytochrome P-450 C-M/F, new constitutive form of microsomal cytochrome P-450 in male and female rat liver with estrogen 2- and 16.alpha.-hydroxylase activity

Cited by 20 publications

References 55 publications

Functional role of estrogen metabolism in target cells: review and perspectives

Functional role of estrogen metabolism in target cells: review and perspectives

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

The rat cytochrome P450 C&hyphen;M/F (CYP2D) subfamily: Constitutive P450 isozymes in male and female

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Cytochrome P-450 C-M/F, new constitutive form of microsomal cytochrome P-450 in male and female rat liver with estrogen 2- and 16.alpha.-hydroxylase activity

Cited by 20 publications

References 55 publications

Functional role of estrogen metabolism in target cells: review and perspectives

Functional role of estrogen metabolism in target cells: review and perspectives

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

The rat cytochrome P450 C&hyphen;M&sol;F &lpar;CYP2D&rpar; subfamily: Constitutive P450 isozymes in male and female

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The rat cytochrome P450 C&hyphen;M/F (CYP2D) subfamily: Constitutive P450 isozymes in male and female