Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa.
Tumour formation may involve interactions between genetic factors and environmental carcinogens. Adenoma formation in APCMin/+ mice is associated homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on carcinogen susceptibility are unknown. This study tests the hypothesis that APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S-transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed in adenomas and uninvolved mucosa from APCMin/+ mice, before and after benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2 and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GSTalpha and pi class enzymes were unaffected. A GST mu band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8) nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These properties could influence mutagenesis and subsequent neoplastic transformation of adenomas.
Sattar
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University Department of Surgery, The Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
Hewer
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Phillips
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DH
Campbell
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FC
D000236:Adenoma / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000633:toxicity; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004790:Enzyme Induction; D017491:Genes, APC; D005982:Glutathione Transferase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
D002274:Carcinogens, Environmental; D018736:DNA Adducts; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D005982:Glutathione Transferase