Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa.

Abstract

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.

• Authors: A Sattar, A Hewer, D H Phillips, F C Campbell
• Journal: Carcinogenesis (Carcinogenesis) Vol. 20 Issue 6 Pg. 1097-101 (Jun 1999) ISSN: 0143-3334 [Print] England
• PMID: 10357794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens, Environmental
• DNA Adducts
• benzo(a)pyrene-DNA adduct
• Benzo(a)pyrene
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2
• Glutathione Transferase

Topics

• Adenoma (enzymology, metabolism)
• Animals
• Benzo(a)pyrene (metabolism)
• Carcinogens, Environmental (toxicity)
• Colonic Neoplasms (enzymology, metabolism)
• Cytochrome P-450 CYP1A1 (biosynthesis, metabolism)
• Cytochrome P-450 CYP1A2 (biosynthesis, metabolism)
• DNA Adducts (metabolism)
• Enzyme Induction
• Genes, APC
• Glutathione Transferase (metabolism)
• Intestinal Mucosa (enzymology, metabolism)
• Mice
• Mice, Inbred C57BL