Influence of β-Naphthoflavone and Methoxychlor Pretreatment on the Biotransformation and Estrogenic Activity of Methoxychlor in Channel Catfish (Ictalurus punctatus)

The organochlorine pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl) ethane] (MXC) has been classified as a proestrogen in mammals and fish, requiring demethylation prior to eliciting estrogenic activity or binding to the estrogen receptor. While microsomal demethylation occurs readil...

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Veröffentlicht in:Toxicology and applied pharmacology 1997-08, Vol.145 (2), p.349-356
Hauptverfasser: Schlenk, Daniel, Stresser, David M., McCants, John C., Nimrod, Alison C., Benson, William H.
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container_issue 2
container_start_page 349
container_title Toxicology and applied pharmacology
container_volume 145
creator Schlenk, Daniel
Stresser, David M.
McCants, John C.
Nimrod, Alison C.
Benson, William H.
description The organochlorine pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl) ethane] (MXC) has been classified as a proestrogen in mammals and fish, requiring demethylation prior to eliciting estrogenic activity or binding to the estrogen receptor. While microsomal demethylation occurs readily in the liver of fish, little is known about the enzyme(s) responsible or the effect of cytochrome P450 (CYP) inducers, other than those of CYP1A and CYP2K, on biotransformation. Consequently, male channel catfish were pretreated with MXC or β-naphthoflavone (BNF), alone and in combination, to determine their effects on CYP protein expression, MXC biotransformation by hepatic microsomes, microsomal protein binding, and MXC estrogenic activity as determined by serum vitellogenin and 17β-estradiol. Liver microsomes of both treated and untreated mature male catfish catalyzed formation of monodemethylated MXC, bisdemethylated MXC, as well as ring-hydroxylated metabolites. Pretreatment with BNF did not affect MXC metabolite profiles, overall rates of MXC biotransformation, or microsomal proteins recognized by anti-trout CYP2K1, but had the expected effect of inducing CYP1A and associated ethoxyresorufinO-deethylase activity. By contrast, pretreatment with MXC, alone or in combination with BNF, significantly reduced rates of MXC biotransformation and binding to liver microsomal protein. MXC/BNF cotreatment followed by MXC significantly induced serum vitellogenin, whereas MXC treatment alone led to a nonsignificant increase in vitellogenin and a significant increase in serum 17β-estradiol. Thus, estrogenic activity elicited by cotreatment with MXC and BNF can occur despite diminished capacity of liver microsomes to catalyze formation of estrogenic demethylated metabolites or metabolites that bind microsomal protein. Possible mechanisms of MXC-induced attenuation of CYP-dependent metabolism are discussed.
doi_str_mv 10.1006/taap.1997.8194
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While microsomal demethylation occurs readily in the liver of fish, little is known about the enzyme(s) responsible or the effect of cytochrome P450 (CYP) inducers, other than those of CYP1A and CYP2K, on biotransformation. Consequently, male channel catfish were pretreated with MXC or β-naphthoflavone (BNF), alone and in combination, to determine their effects on CYP protein expression, MXC biotransformation by hepatic microsomes, microsomal protein binding, and MXC estrogenic activity as determined by serum vitellogenin and 17β-estradiol. Liver microsomes of both treated and untreated mature male catfish catalyzed formation of monodemethylated MXC, bisdemethylated MXC, as well as ring-hydroxylated metabolites. Pretreatment with BNF did not affect MXC metabolite profiles, overall rates of MXC biotransformation, or microsomal proteins recognized by anti-trout CYP2K1, but had the expected effect of inducing CYP1A and associated ethoxyresorufinO-deethylase activity. 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By contrast, pretreatment with MXC, alone or in combination with BNF, significantly reduced rates of MXC biotransformation and binding to liver microsomal protein. MXC/BNF cotreatment followed by MXC significantly induced serum vitellogenin, whereas MXC treatment alone led to a nonsignificant increase in vitellogenin and a significant increase in serum 17β-estradiol. Thus, estrogenic activity elicited by cotreatment with MXC and BNF can occur despite diminished capacity of liver microsomes to catalyze formation of estrogenic demethylated metabolites or metabolites that bind microsomal protein. Possible mechanisms of MXC-induced attenuation of CYP-dependent metabolism are discussed.</description><subject>ACTIVADOR ENZIMATICO</subject><subject>ACTIVATEUR D'ENZYME</subject><subject>ACTIVIDAD ENZIMATICA</subject><subject>ACTIVITE ENZYMATIQUE</subject><subject>Animals</subject><subject>beta-Naphthoflavone - administration &amp; dosage</subject><subject>beta-Naphthoflavone - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biotransformation - drug effects</subject><subject>BLOOD SERUM</subject><subject>CITOCROMO P450</subject><subject>Cytochrome P-450 Enzyme System - biosynthesis</subject><subject>CYTOCHROME P450</subject><subject>CYTOPLASMIC ORGANELLES</subject><subject>ENZYME ACTIVATORS</subject><subject>Enzyme Induction - drug effects</subject><subject>ENZYMIC ACTIVITY</subject><subject>Estradiol - blood</subject><subject>ESTROGENIC PROPERTIES</subject><subject>ESTROGENOS</subject><subject>Estrogens - blood</subject><subject>FLAVONOIDE</subject><subject>FLAVONOIDES</subject><subject>FLAVONOIDS</subject><subject>FOIE</subject><subject>Freshwater</subject><subject>HIGADO</subject><subject>Ictaluridae</subject><subject>ICTALURUS</subject><subject>Ictalurus punctatus</subject><subject>Injections, Intraperitoneal</subject><subject>LIVER</subject><subject>Male</subject><subject>Medical sciences</subject><subject>METABOLISM</subject><subject>METABOLISME</subject><subject>METABOLISMO</subject><subject>METABOLITE</subject><subject>METABOLITES</subject><subject>METABOLITOS</subject><subject>METHOXYCHLOR</subject><subject>Methoxychlor - administration &amp; 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dosage</topic><topic>Methoxychlor - pharmacokinetics</topic><topic>Methoxychlor - pharmacology</topic><topic>METHOXYCHLORE</topic><topic>METOXICLORO</topic><topic>MICROSOMES</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>OESTROGENE</topic><topic>OESTROGENS</topic><topic>ORGANITE CELLULAIRE</topic><topic>ORGANULOS CITOPLASMICOS</topic><topic>OXIDOREDUCTASES</topic><topic>OXIDORREDUCTASAS</topic><topic>OXYDOREDUCTASE</topic><topic>Pesticides, fertilizers and other agrochemicals toxicology</topic><topic>SERUM SANGUIN</topic><topic>SUERO SANGUINEO</topic><topic>Toxicology</topic><topic>UNSPECIFIC MONOOXYGENASE</topic><topic>VITELLOGENINE</topic><topic>VITELLOGENINS</topic><topic>Vitellogenins - blood</topic><topic>VITELOGENINA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schlenk, Daniel</creatorcontrib><creatorcontrib>Stresser, David M.</creatorcontrib><creatorcontrib>McCants, John C.</creatorcontrib><creatorcontrib>Nimrod, Alison C.</creatorcontrib><creatorcontrib>Benson, William H.</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Water Resources Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) 3: Aquatic Pollution &amp; Environmental Quality</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) Professional</collection><collection>MEDLINE - Academic</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schlenk, Daniel</au><au>Stresser, David M.</au><au>McCants, John C.</au><au>Nimrod, Alison C.</au><au>Benson, William H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of β-Naphthoflavone and Methoxychlor Pretreatment on the Biotransformation and Estrogenic Activity of Methoxychlor in Channel Catfish (Ictalurus punctatus)</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>1997-08-01</date><risdate>1997</risdate><volume>145</volume><issue>2</issue><spage>349</spage><epage>356</epage><pages>349-356</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>The organochlorine pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl) ethane] (MXC) has been classified as a proestrogen in mammals and fish, requiring demethylation prior to eliciting estrogenic activity or binding to the estrogen receptor. While microsomal demethylation occurs readily in the liver of fish, little is known about the enzyme(s) responsible or the effect of cytochrome P450 (CYP) inducers, other than those of CYP1A and CYP2K, on biotransformation. Consequently, male channel catfish were pretreated with MXC or β-naphthoflavone (BNF), alone and in combination, to determine their effects on CYP protein expression, MXC biotransformation by hepatic microsomes, microsomal protein binding, and MXC estrogenic activity as determined by serum vitellogenin and 17β-estradiol. Liver microsomes of both treated and untreated mature male catfish catalyzed formation of monodemethylated MXC, bisdemethylated MXC, as well as ring-hydroxylated metabolites. Pretreatment with BNF did not affect MXC metabolite profiles, overall rates of MXC biotransformation, or microsomal proteins recognized by anti-trout CYP2K1, but had the expected effect of inducing CYP1A and associated ethoxyresorufinO-deethylase activity. By contrast, pretreatment with MXC, alone or in combination with BNF, significantly reduced rates of MXC biotransformation and binding to liver microsomal protein. MXC/BNF cotreatment followed by MXC significantly induced serum vitellogenin, whereas MXC treatment alone led to a nonsignificant increase in vitellogenin and a significant increase in serum 17β-estradiol. Thus, estrogenic activity elicited by cotreatment with MXC and BNF can occur despite diminished capacity of liver microsomes to catalyze formation of estrogenic demethylated metabolites or metabolites that bind microsomal protein. Possible mechanisms of MXC-induced attenuation of CYP-dependent metabolism are discussed.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>9266808</pmid><doi>10.1006/taap.1997.8194</doi><tpages>8</tpages></addata></record>
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identifier ISSN: 0041-008X
ispartof Toxicology and applied pharmacology, 1997-08, Vol.145 (2), p.349-356
issn 0041-008X
1096-0333
language eng
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subjects ACTIVADOR ENZIMATICO
ACTIVATEUR D'ENZYME
ACTIVIDAD ENZIMATICA
ACTIVITE ENZYMATIQUE
Animals
beta-Naphthoflavone - administration & dosage
beta-Naphthoflavone - pharmacology
Biological and medical sciences
Biotransformation - drug effects
BLOOD SERUM
CITOCROMO P450
Cytochrome P-450 Enzyme System - biosynthesis
CYTOCHROME P450
CYTOPLASMIC ORGANELLES
ENZYME ACTIVATORS
Enzyme Induction - drug effects
ENZYMIC ACTIVITY
Estradiol - blood
ESTROGENIC PROPERTIES
ESTROGENOS
Estrogens - blood
FLAVONOIDE
FLAVONOIDES
FLAVONOIDS
FOIE
Freshwater
HIGADO
Ictaluridae
ICTALURUS
Ictalurus punctatus
Injections, Intraperitoneal
LIVER
Male
Medical sciences
METABOLISM
METABOLISME
METABOLISMO
METABOLITE
METABOLITES
METABOLITOS
METHOXYCHLOR
Methoxychlor - administration & dosage
Methoxychlor - pharmacokinetics
Methoxychlor - pharmacology
METHOXYCHLORE
METOXICLORO
MICROSOMES
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
OESTROGENE
OESTROGENS
ORGANITE CELLULAIRE
ORGANULOS CITOPLASMICOS
OXIDOREDUCTASES
OXIDORREDUCTASAS
OXYDOREDUCTASE
Pesticides, fertilizers and other agrochemicals toxicology
SERUM SANGUIN
SUERO SANGUINEO
Toxicology
UNSPECIFIC MONOOXYGENASE
VITELLOGENINE
VITELLOGENINS
Vitellogenins - blood
VITELOGENINA
title Influence of β-Naphthoflavone and Methoxychlor Pretreatment on the Biotransformation and Estrogenic Activity of Methoxychlor in Channel Catfish (Ictalurus punctatus)
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