CYP1A induction by beta-naphthoflavone, Aroclor 1254, and 2,3,7,8-tetrachlorodibenzo-p-dioxin and its influence on aflatoxin B1 metabolism and DNA adduction in zebrafish. 1997

C M Troxel, and D R Buhler, and J D Hendricks, and G S Bailey
Toxicology Program, Oregon State University, Corvallis, Oregon, 97331, USA.

This study investigated the inductive response of cytochrome P4501A (CYP1A) in the zebrafish (Danio rerio) following exposure to Aroclor 1254, beta-naphthoflavone (betaNF), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and then investigated TCDD modulation of aflatoxin B1 (AFB1) metabolism and hepatic AFB1-DNA adduction. Aroclor 1254 fed at 500 ppm for 1 to 9 days or intraperitoneal (ip) injection of 75-200 mg Aroclor 1254/kg body weight failed to induce CYP1A protein or associated 7-ethoxyresorufin-O-deethylase (EROD) activity. By contrast, dietary betaNF at 500 ppm for 3 or 7 days induced CYP1A protein and EROD activity approximately threefold above controls. A single ip injection of 150 mg/kg betaNF showed maximal induction of CYP1A protein and EROD activity near 24 hr, both of which decreased to control levels during the next 6 days. Single ip administration of 25, 50, 100, or 150 mg betaNF/kg body weight provided dose-responsive increases in CYP1A and EROD activity. Dietary exposure to 0.75 ppm TCDD for 3 days also significantly induced CYP1A and EROD. The effect of TCDD on the metabolism of [3H]AFB1 in zebrafish was then investigated. The major [3H]AFB1 metabolites excreted in water over 24 hr in the control group were aflatoxicol, aflatoxicol-glucuronide, and parent AFB1. By contrast, the predominant metabolites in the TCDD-pretreated group were aflatoxicol-M1-glucuronide, aflatoxicol, aflatoxin M1 plus aflatoxicol-M1 (unresolved), aflatoxicol-glucuronide, and parent AFB1. Surprisingly, hepatic AFB1-DNA adduction was approximately fourfold higher in the TCDD treated group than in controls. This significant difference could not be explained by increased capacity for bioactivation of AFB1 as measured by an in vitro AFB1-exo-8, 9-epoxide trapping assay. However, it was demonstrated that both control and induced zebrafish have high capacity to bioactivate aflatoxin M1 to a reactive intermediate, such that secondary bioactivation of this genotoxic intermediate may be responsible for the increased DNA binding.

UI MeSH Term Description Entries
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D000072317 Polychlorinated Dibenzodioxins Dibenzodioxin derivatives that contain multiple chloride atoms bound to the benzene ring structures. TCDD,Tetrachlorodibenzodioxin,2,3,7,8-Tetrachlorodibenzo-p-dioxin,Chlorinated Dibenzo-p-dioxins,Dibenzo(b,e)(1,4)dioxin, 2,3,7,8-tetrachloro-,PCDD,Polychlorinated Dibenzo-p-dioxins,Polychlorinated Dibenzodioxin,Polychlorodibenzo-4-dioxin,Polychlorodibenzo-p-dioxin,Tetrachlorodibenzo-p-dioxin,Chlorinated Dibenzo p dioxins,Dibenzo-p-dioxins, Chlorinated,Dibenzo-p-dioxins, Polychlorinated,Dibenzodioxin, Polychlorinated,Dibenzodioxins, Polychlorinated,Polychlorinated Dibenzo p dioxins,Polychlorodibenzo 4 dioxin,Polychlorodibenzo p dioxin,Tetrachlorodibenzo p dioxin
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001140 Aroclors Industrial chemicals which have become widespread environmental pollutants. Each aroclor is a mixture of chlorinated biphenyls (1200 series) or chlorinated terphenyls (5400 series) or a combination of both (4400 series). Aroclor
D015027 Zebrafish An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research. Brachydanio rerio,Danio rerio,B. rerio,D. rerio,Zebra Fish,Zebra Fishes,Zebra danio,Zebrafishes,D. rerios,Fishes, Zebra,Zebra danios,danio, Zebra
D016604 Aflatoxin B1 A potent hepatotoxic and hepatocarcinogenic mycotoxin produced by the Aspergillus flavus group of fungi. It is also mutagenic, teratogenic, and causes immunosuppression in animals. It is found as a contaminant in peanuts, cottonseed meal, corn, and other grains. The mycotoxin requires epoxidation to aflatoxin B1 2,3-oxide for activation. Microsomal monooxygenases biotransform the toxin to the less toxic metabolites aflatoxin M1 and Q1. Aflatoxin B(1),Aflatoxin B,Aflatoxin B1 Dihydrochloride, (6aR-cis)-Isomer,Aflatoxin B1, (6aR-cis)-Isomer, 14C-Labeled,Aflatoxin B1, (6aR-cis)-Isomer, 2H-Labeled,Aflatoxin B1, (6aR-cis)-Isomer, 3H-Labeled,Aflatoxin B1, cis(+,-)-Isomer,HSDB-3453,NSC-529592,HSDB 3453,HSDB3453,NSC 529592,NSC529592
D016607 Aflatoxin M1 A 4-hydroxylated metabolite of AFLATOXIN B1, one of the MYCOTOXINS from ASPERGILLUS tainted food. It is associated with LIVER damage and cancer resulting from its P450 activation to the epoxide which alkylates DNA. Toxicity depends on the balance of liver enzymes that activate it (CYTOCHROME P-450) and others that detoxify it (GLUTATHIONE S TRANSFERASE) (Pharmac Ther 50.443 1991). Primates & rat are sensitive while mouse and hamster are tolerant (Canc Res 29.236 1969). Aflatoxin M(1),4-Hydroxyaflatoxin B1,Aflatoxin M,Aflatoxin M1, cis(+-)-Isomer,4 Hydroxyaflatoxin B1
D018736 DNA Adducts The products of chemical reactions that result in the addition of extraneous chemical groups to DNA. DNA Adduct,Adduct, DNA,Adducts, DNA
D019324 beta-Naphthoflavone A polyaromatic hydrocarbon inducer of P4501A1 and P4501A2 cytochromes. (Proc Soc Exp Biol Med 1994 Dec:207(3):302-308) 5,6-Benzoflavone,5,6 Benzoflavone,beta Naphthoflavone

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