Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation

Comparison with nadph-dependent mechanism

Quang Bui, Judith Weisz

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Exogenous aromatic polycyclic hydrocarbons, notably benzo[a]pyrene, can be metabolized by both NADPH-dependent monooxygenase(s) and an organic hydroperoxide (OHP)-dependent mechanism. To determine whether phenolic estrogens, endogenous aromatic polycyclic hydrocarbons, can also be hydroxylated by these alternative pathways, conversion of estradiol (E2) to 2 and 4-hydroxylated catecholestrogens (2 and 4-OH-CEs) by human placental microsomes was examined under conditions previously shown to support CE formation by NADPH and OHP-dependent mechanisms. CEs were formed under both conditions. Properties of OHP-dependent activity were similar to CE formation by peroxidases and distinct from the NADPH-dependent monooxygenase. NADPH supported only 2-hydroxylation, whereas cumene hydroperoxide supported 2 and 4-hydroxylation equally. Monooxygenase-mediated activity had characteristics of a high-affinity, low-capacity enzyme system (apparent Km for E2 = 0.3 μM, and Vmax = 31 pmol/mg protein/30 min). Whereas peroxidatic activity had properties of low affinity and high capacity (apparent Km for E2 = 55 μM, Vmax = 666 pmol/mg protein/10 min). The requirement of peroxidatic activity for oxidizing co-substrate could be met by OHPs but not by H2O2. Peroxidatic CE formation could have special functional significance for physiological and pathological consequences of estrogen action since it generates 4-OH-CEs which are both effective catechols and potent, long-acting estrogens. Moreover, it could provide a link through co-oxygenation between estrogens and diverse cellular mechanisms involving generation of OHPs.

Original languageEnglish (US)
Pages (from-to)356-364
Number of pages9
JournalPharmacology
Volume36
Issue number5
DOIs
StatePublished - Jan 1 1988

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Catechol Estrogens
Hydrogen Peroxide
Estrogens
Mixed Function Oxygenases
NADP
Polycyclic Aromatic Hydrocarbons
Hydroxylation
Catechols
Benzo(a)pyrene
Microsomes
Estradiol
Proteins
Enzymes

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation: Comparison with nadph-dependent mechanism",
abstract = "Exogenous aromatic polycyclic hydrocarbons, notably benzo[a]pyrene, can be metabolized by both NADPH-dependent monooxygenase(s) and an organic hydroperoxide (OHP)-dependent mechanism. To determine whether phenolic estrogens, endogenous aromatic polycyclic hydrocarbons, can also be hydroxylated by these alternative pathways, conversion of estradiol (E2) to 2 and 4-hydroxylated catecholestrogens (2 and 4-OH-CEs) by human placental microsomes was examined under conditions previously shown to support CE formation by NADPH and OHP-dependent mechanisms. CEs were formed under both conditions. Properties of OHP-dependent activity were similar to CE formation by peroxidases and distinct from the NADPH-dependent monooxygenase. NADPH supported only 2-hydroxylation, whereas cumene hydroperoxide supported 2 and 4-hydroxylation equally. Monooxygenase-mediated activity had characteristics of a high-affinity, low-capacity enzyme system (apparent Km for E2 = 0.3 μM, and Vmax = 31 pmol/mg protein/30 min). Whereas peroxidatic activity had properties of low affinity and high capacity (apparent Km for E2 = 55 μM, Vmax = 666 pmol/mg protein/10 min). The requirement of peroxidatic activity for oxidizing co-substrate could be met by OHPs but not by H2O2. Peroxidatic CE formation could have special functional significance for physiological and pathological consequences of estrogen action since it generates 4-OH-CEs which are both effective catechols and potent, long-acting estrogens. Moreover, it could provide a link through co-oxygenation between estrogens and diverse cellular mechanisms involving generation of OHPs.",
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Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation : Comparison with nadph-dependent mechanism. / Bui, Quang; Weisz, Judith.

In: Pharmacology, Vol. 36, No. 5, 01.01.1988, p. 356-364.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation

T2 - Comparison with nadph-dependent mechanism

AU - Bui, Quang

AU - Weisz, Judith

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Y1 - 1988/1/1

N2 - Exogenous aromatic polycyclic hydrocarbons, notably benzo[a]pyrene, can be metabolized by both NADPH-dependent monooxygenase(s) and an organic hydroperoxide (OHP)-dependent mechanism. To determine whether phenolic estrogens, endogenous aromatic polycyclic hydrocarbons, can also be hydroxylated by these alternative pathways, conversion of estradiol (E2) to 2 and 4-hydroxylated catecholestrogens (2 and 4-OH-CEs) by human placental microsomes was examined under conditions previously shown to support CE formation by NADPH and OHP-dependent mechanisms. CEs were formed under both conditions. Properties of OHP-dependent activity were similar to CE formation by peroxidases and distinct from the NADPH-dependent monooxygenase. NADPH supported only 2-hydroxylation, whereas cumene hydroperoxide supported 2 and 4-hydroxylation equally. Monooxygenase-mediated activity had characteristics of a high-affinity, low-capacity enzyme system (apparent Km for E2 = 0.3 μM, and Vmax = 31 pmol/mg protein/30 min). Whereas peroxidatic activity had properties of low affinity and high capacity (apparent Km for E2 = 55 μM, Vmax = 666 pmol/mg protein/10 min). The requirement of peroxidatic activity for oxidizing co-substrate could be met by OHPs but not by H2O2. Peroxidatic CE formation could have special functional significance for physiological and pathological consequences of estrogen action since it generates 4-OH-CEs which are both effective catechols and potent, long-acting estrogens. Moreover, it could provide a link through co-oxygenation between estrogens and diverse cellular mechanisms involving generation of OHPs.

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