Role of hepatic and intestinal P450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice

Vandana Megaraj, Xinxin Ding, Cheng Fang, Nataliia Kovalchuk, Yi Zhu, Qing Yu Zhang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

P450-mediated bioactivation of azoxymethane (AOM), a colon carcinogen, leads to the formation of DNA adducts, of which O6-methylguanine (O6-mG) is the most mutagenic and contributes to colon tumorigenesis. To determine whether P450 enzymes of the liver and intestine both contribute to AOM bioactivation in vivo, we compared tissue levels of AOM-induced DNA adducts, microsomal AOM metabolic activities, and incidences of colonic aberrant crypt foci (ACF) among wild-type (WT), liver-specific P450 reductase (Cpr)-null (LCN), and intestinal epithelium-specific Cpr-null (IECN) mice. At 6 h following AOM treatment (at 14 mg/kg, s.c.), O6-mG and N 7-mG levels were highest in the liver, followed by the colon, and then small intestine in WT mice. As expected, hepatic adduct levels were significantly lower (by >60%) in LCN mice but unchanged in IECN mice, whereas small-intestinal adduct levels were unchanged or increased in LCN mice but lower (by >50%) in IECN mice compared to that in WT mice. However, colonic adduct levels were unchanged in IECN mice compared to that in WT mice and increased in LCN mice (by 1.5-2.9-fold). The tissue-specific impact of the CPR loss in IECN and LCN mice on microsomal AOM metabolic activity was confirmed by rates of formation of formaldehyde and N7-mG in vitro. Furthermore, the incidence of ACF, a lesion preceding colon cancer, was similar in the three mouse strains. Thus, AOM-induced colonic DNA damage and ACF formation is not solely dependent on either hepatic or intestinal microsomal P450 enzymes. P450 enzymes in both the liver and intestine likely contribute to AOM-induced colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)656-662
Number of pages7
JournalChemical Research in Toxicology
Volume27
Issue number4
DOIs
StatePublished - Apr 21 2014
Externally publishedYes

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Azoxymethane
Carcinogens
Cytochrome P-450 Enzyme System
Colon
Chemical activation
Liver
Intestinal Mucosa
Aberrant Crypt Foci
DNA Adducts
Tissue
Intestines
Metabolic Activation
Carcinogenesis
Formaldehyde
Oxidoreductases
Incidence
Cardiopulmonary Resuscitation
Colonic Neoplasms
DNA Damage
Small Intestine

ASJC Scopus subject areas

  • Toxicology

Cite this

Role of hepatic and intestinal P450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice. / Megaraj, Vandana; Ding, Xinxin; Fang, Cheng; Kovalchuk, Nataliia; Zhu, Yi; Zhang, Qing Yu.

In: Chemical Research in Toxicology, Vol. 27, No. 4, 21.04.2014, p. 656-662.

Research output: Contribution to journalArticle

Megaraj, Vandana ; Ding, Xinxin ; Fang, Cheng ; Kovalchuk, Nataliia ; Zhu, Yi ; Zhang, Qing Yu. / Role of hepatic and intestinal P450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice. In: Chemical Research in Toxicology. 2014 ; Vol. 27, No. 4. pp. 656-662.
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abstract = "P450-mediated bioactivation of azoxymethane (AOM), a colon carcinogen, leads to the formation of DNA adducts, of which O6-methylguanine (O6-mG) is the most mutagenic and contributes to colon tumorigenesis. To determine whether P450 enzymes of the liver and intestine both contribute to AOM bioactivation in vivo, we compared tissue levels of AOM-induced DNA adducts, microsomal AOM metabolic activities, and incidences of colonic aberrant crypt foci (ACF) among wild-type (WT), liver-specific P450 reductase (Cpr)-null (LCN), and intestinal epithelium-specific Cpr-null (IECN) mice. At 6 h following AOM treatment (at 14 mg/kg, s.c.), O6-mG and N 7-mG levels were highest in the liver, followed by the colon, and then small intestine in WT mice. As expected, hepatic adduct levels were significantly lower (by >60{\%}) in LCN mice but unchanged in IECN mice, whereas small-intestinal adduct levels were unchanged or increased in LCN mice but lower (by >50{\%}) in IECN mice compared to that in WT mice. However, colonic adduct levels were unchanged in IECN mice compared to that in WT mice and increased in LCN mice (by 1.5-2.9-fold). The tissue-specific impact of the CPR loss in IECN and LCN mice on microsomal AOM metabolic activity was confirmed by rates of formation of formaldehyde and N7-mG in vitro. Furthermore, the incidence of ACF, a lesion preceding colon cancer, was similar in the three mouse strains. Thus, AOM-induced colonic DNA damage and ACF formation is not solely dependent on either hepatic or intestinal microsomal P450 enzymes. P450 enzymes in both the liver and intestine likely contribute to AOM-induced colon carcinogenesis.",
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