Novel metabolic pathways of p-n-nonylphenol catalyzed by cytochrome P450 and estrogen receptor binding activity of new metabolites

Yoshito Tezuka, Kyoko Takahashi, Tomoharu Suzuki, Shigeyuki Kitamura, Shigeru Ohta, Shigeo Nakamura, Tadahiko Mashino

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4′- hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4′-hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CONP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.

Original languageEnglish
Pages (from-to)552-561
Number of pages10
JournalJournal of Health Science
Volume53
Issue number5
DOIs
Publication statusPublished - 2007 Oct

Fingerprint

Metabolites
Metabolic Networks and Pathways
Estrogen Receptors
Cytochrome P-450 Enzyme System
Carbon Monoxide
Cytochrome P-450 CYP1A1
Liver Microsomes
Metabolism
Liver
Isoenzymes
Endocrine Disruptors
Hydroxylation
nonylphenol
Phenols
Biotransformation
Reporter Genes
Surface-Active Agents
Rats
Assays
Genes

Keywords

  • Cytochrome P450
  • Endocrine disruptor
  • Estrogenic activity
  • Metabolism
  • Nonylphenol

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Novel metabolic pathways of p-n-nonylphenol catalyzed by cytochrome P450 and estrogen receptor binding activity of new metabolites. / Tezuka, Yoshito; Takahashi, Kyoko; Suzuki, Tomoharu; Kitamura, Shigeyuki; Ohta, Shigeru; Nakamura, Shigeo; Mashino, Tadahiko.

In: Journal of Health Science, Vol. 53, No. 5, 10.2007, p. 552-561.

Research output: Contribution to journalArticle

Tezuka, Yoshito ; Takahashi, Kyoko ; Suzuki, Tomoharu ; Kitamura, Shigeyuki ; Ohta, Shigeru ; Nakamura, Shigeo ; Mashino, Tadahiko. / Novel metabolic pathways of p-n-nonylphenol catalyzed by cytochrome P450 and estrogen receptor binding activity of new metabolites. In: Journal of Health Science. 2007 ; Vol. 53, No. 5. pp. 552-561.
@article{e1f80b98a3494ee789424e3e9296b007,
title = "Novel metabolic pathways of p-n-nonylphenol catalyzed by cytochrome P450 and estrogen receptor binding activity of new metabolites",
abstract = "Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4′- hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4′-hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CONP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.",
keywords = "Cytochrome P450, Endocrine disruptor, Estrogenic activity, Metabolism, Nonylphenol",
author = "Yoshito Tezuka and Kyoko Takahashi and Tomoharu Suzuki and Shigeyuki Kitamura and Shigeru Ohta and Shigeo Nakamura and Tadahiko Mashino",
year = "2007",
month = "10",
doi = "10.1248/jhs.53.552",
language = "English",
volume = "53",
pages = "552--561",
journal = "Journal of Health Science",
issn = "1344-9702",
publisher = "Pharmaceutical Society of Japan",
number = "5",

}

TY - JOUR

T1 - Novel metabolic pathways of p-n-nonylphenol catalyzed by cytochrome P450 and estrogen receptor binding activity of new metabolites

AU - Tezuka, Yoshito

AU - Takahashi, Kyoko

AU - Suzuki, Tomoharu

AU - Kitamura, Shigeyuki

AU - Ohta, Shigeru

AU - Nakamura, Shigeo

AU - Mashino, Tadahiko

PY - 2007/10

Y1 - 2007/10

N2 - Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4′- hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4′-hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CONP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.

AB - Nonylphenol, which is used industrially as a surfactant, is an endocrine-disrupting chemical (EDC) which has estrogenic activity. The novel biotransformation of nonylphenol was investigated, based on our previously reported ipso-metabolism of para-substituted phenols by cytochrome P450 (P450). Three novel metabolites of nonylphenol, i.e., nonylquinol, 4′- hydroxynonanophenone (CO-NP) as benzyl-oxidized nonylphenol, and hydroquinone, were detected in a rat liver microsome reaction mixture. On the other hand, production of 1-(4′-hydroxyphenyl)nonan-1-ol (OH-NP), namely benzyl-hydroxylated nonylphenol, was detected in a human liver microsome reaction mixture. The formation of all these metabolites was suppressed by the addition of P450 inhibitor. This showed that all nonylphenol metabolism was catalyzed by P450. To identify which P450 isoenzyme is involved in each reaction, fourteen human P450 (CYP) isozymes, CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and CYP4A11, were examined. CYP1A1, 1A2, and CYP2B6 effectively catalyzed the production of nonylquinol. CYP2B6 also catalyzed the benzyl-hydroxylation to give OH-NP. Hydroquinone was formed mainly from OH-NP, not via CO-NP. We examined the estrogenic activity of these new metabolites by estrogen receptor (ER)-binding reporter gene assay. Nonylquinol, OH-NP and hydroquinone have no ER-binding activity. However, CO-NP showed the same level of estrogen receptor binding activity as nonylphenol. Moreover, the amount of CONP formed was small. Therefore, the novel metabolic pathways led overall to metabolic inactivation, as concerns the estrogenic activity of nonylphenol through the ER.

KW - Cytochrome P450

KW - Endocrine disruptor

KW - Estrogenic activity

KW - Metabolism

KW - Nonylphenol

UR - http://www.scopus.com/inward/record.url?scp=35148848734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35148848734&partnerID=8YFLogxK

U2 - 10.1248/jhs.53.552

DO - 10.1248/jhs.53.552

M3 - Article

VL - 53

SP - 552

EP - 561

JO - Journal of Health Science

JF - Journal of Health Science

SN - 1344-9702

IS - 5

ER -