17<i>β</i>-Estradiol 2- and 4-Hydroxylation Catalyzed by Rat Hepatic Cytochrome P-450: Roles of Individual Forms, Inductive Effects, Developmental Patterns, and Alterations by Gonadectomy and Hormone Replacement*

Dannan, Ghazi A.; Porubek, David J.; Nelson, Sidney D.; Waxman, David J.; Guengerich, F. Peter

doi:10.1210/endo-118-5-1952

Cited by 125 publications

(44 citation statements)

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“…38 Expression of CYP1A1/2, as assessed by immunohistochemistry, was detected in a minority of breast cancers only, according to former studies reporting low CYP1A1 mRNA expression levels in neoplastic and nonneoplastic breast tissue. 22,39 Even in this small group of cancers, expression was not associated with any clinical or histochemical features, including ER status.…”

Section: Discussionmentioning

confidence: 99%

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

Haas

Pierl

Harth

et al. 2006

Intl Journal of Cancer

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The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p 5 0.018) and with reduced lymph node metastasis (GST pi, p 5 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p < 0.001). CYP3A4/5 expression was associated with a positive nodal status (p 5 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p 5 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis. ' 2006 Wiley-Liss, Inc.Key words: breast carcinoma; GST; CYP; immunohistochemistry; estrogen receptor; progesterone receptor The influence of exogenous and endogenous factors on tumor growth partly depends on the individual potential to metabolize these substances. Phase I and phase II enzymes are key players in the metabolism of a huge number of exogenous and endogenous compounds including steroid hormones. Usually, phase I and phase II are detoxification processes, but this metabolism can also lead to highly reactive electrophiles that can bind to macromolecules, e.g., proteins and DNA. Moreover, these enzymes are highly polymorphic, giving rise to variations in enzymatic activity.1 This may influence predisposition to cancer as well as tumor development and progression.2 Therefore, these enzymes are candidates for the investigation of a potential role in breast cancer.Glutathione S-transferases (GSTs) are phase II metabolizing isoenzymes. They facilitate clearance of endogenous hydrophobic compounds such as hormones, steroids, haem, bilirubin and bile acids. Furthermore, they are essential for metabolism of environmental carcinogens, drugs and pesticides by catalyzing the conjunction of reactive chemical intermediates to soluble glutathione conjugates.3 Seven classes of cytosolic GSTs are recognized in mammalian tissues (alpha, mu, pi, sigma, om...

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Section: Discussionmentioning

confidence: 99%

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

Haas

Pierl

Harth

et al. 2006

Intl Journal of Cancer

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“…A modification of the procedure of Dannan et al [7] based on the tritiated water method was used to determine estrogen 2-hydroxylase activity as previously reported [8]. Human placental microsomes (0.5 mg protein) were incubated for 20 min at 37 °C with [2-3H]estradiol (1.5 x 105 dpm 3H/ ,ug, 5 pM) as substrate in the presence of NAD-PH (0.75 mM) in a total volume of 1.0 ml of 0.1 M phosphate buffer (pH 7.6).…”

Section: -Hydroxylase Assaymentioning

confidence: 99%

“…Microsomal 2-hydroxylation of estradiol by human term placenta was first described by Fishman and Dixon in 1967 [5], but the specific cytochrome P450s responsible for this conversion have not been identified. But estrogen 2-hydroxylation by human placental microsomes is believed to also be catalyzed by a distinct cytochrome P450 enzyme [7]. Recently, the capacity of estrogen 2-hydroxylase activity in the human placental aromatase has been described [8].…”

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confidence: 99%

Aromatase and Estrogen 2-Hydroxylase Activities of Human Placental Microsomes in Pregnancy-Induced Hypertension.

et al. 1996

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Abstract. 2-Hydroxylationis one of the major metabolic pathways of estrogens and is believed to be catalyzed by a form of cytochrome P450. Recently it has been reported that estrogen 2-hydroxylase activity in human placenta is catalyzed by aromatase.Some investigators suggested the effect of catechol estrogen on human placental steroidogenesis which may be related to pregnancy-induced hypertension (PIH) through the inhibition of catechol-0-methyltransferase (COMT) activity. In order to better understand the interrelationship between placental aromatase and estrogen 2-hydroxylase activities in PIH patients, both activities were evaluated in the PIH placentas.Human placental microsomes obtained from PIH patients were incubated with [1/3-3H]androstenedione or [2-3H]estradiol in the presence of NADPH. Aromatase and estrogen 2-hydroxylase activities were assessed by the tritium water method. The immunosuppression patterns of both activities due to monoclonal antiaromatase cytochrome P450 antibody (MAb3-2C2) were studied. Estrogen 2-hydroxylase activity was significantly higher in PIH placentas (4.7 ± 0.9 pmol/min/mg protein, n=7) than in normal placentas (3.0 ± 0.7 pmol/min/mg protein, n=7). When the PIH placental microsomes were subjected to immunosuppression by 1 to 100 µg IgG of MAb3-2C2, estrogen 2-hydroxylase activity was suppressed by 94 to 65% whereas aromatase activity was strongly suppressed by 72 to 17%, respectively. From our results of high estrogen 2-hydroxylase activity in PIH placentas, it is assumed that there is a different estrogen catalyzing mechanism in PIH placentas.

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“…In mammal, hepatic CYP catalyzes NADPH-dependent oxidation of estrogens to various hydroxylated or keto metabolites (Zhu and Conney, 1998, Review). 2-Hydroxylation is the major microsomal metabolic pathway of E2 in the liver of all mammalian species including humans (Dannan et al, 1986;Hammond et al, 1997;Zhu and Conney, 1998;Badawi et al, 2001). In the oxidation of E2 by liver microsomes of female Sprague-Dawley rats 4-hydroxylation is only a minor pathway (Mesia-Vela et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Suppression of Bisphenol A on Estradiol 2- and 4-Hydroxylase Activities in Hepatic Microsomal Fractions of Male and Female Sprague-Dawley Rats

Nugraha¹,

Yoon²,

Kandagaddala³

et al. 2009

Biomolecules and Therapeutics

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-This work was conducted to investigate the effect of bisphenol A (BPA) on estradiol (E2) 2-and 4-hydroxylase activities in the liver, kidney and lung tissues of male and female rats. After intraperitoneal administration of BPA to male and female rats for 4 days at 0, 10, and 50 mg/kg, the conversion of the substrate for hepatic and extra-hepatic enzyme activities was measured by GC/MSD. The result showed decreases of body and organ weights at 50 mg/kg BPA of male and female rats. Male hepatic E2 2-hydroxylase activity was inhibited by 68% at 10 mg/kg and by 82% at 50 mg/kg BPA. Female hepatic E2 2-hydroxylase activity was decreased by 46% at 10 mg/kg and by 56% at 50 mg/kg to the control. E2 4-hydroxylase was inhibited by 57 and 57% at 10 mg/kg and 54 and 78% at 50 mg/kg in liver of female and male, respectively. The urinary excretion rate of 2-hydroxyestradiol (2-OHE), androsterone and testosterone in urine of female rats with 50 mg/kg BPA were decreased significantly. The results showed that 50 mg/kg BPA was decreased E2 2-and 4-hydroxylase activities in liver, but not in other tissues. The urinary excretion rates of 2-OHE, androsterone and testosterone were also decreased. In liver, estrogenic enzyme activity were higher in male than female. These results suggest that BPA can disrupt estrogen metabolism by suppressing E2 2-and 4-hydroxylase activities in the liver of male and female rats.

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17β-Estradiol 2- and 4-Hydroxylation Catalyzed by Rat Hepatic Cytochrome P-450: Roles of Individual Forms, Inductive Effects, Developmental Patterns, and Alterations by Gonadectomy and Hormone Replacement*

Cited by 125 publications

References 0 publications

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

Aromatase and Estrogen 2-Hydroxylase Activities of Human Placental Microsomes in Pregnancy-Induced Hypertension.

In Vivo Suppression of Bisphenol A on Estradiol 2- and 4-Hydroxylase Activities in Hepatic Microsomal Fractions of Male and Female Sprague-Dawley Rats

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