Carcinogenesis, Vol. 20, No. 6, 1097-1101,
June 1999
© 1999 Oxford University Press
Carcinogenesis |
Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa
University Department of Surgery, The Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK and
1 Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK
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)
, µ and 
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 GST, µ and class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GST and class enzymes were unaffected. A GSTµ band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GST and , to high levels. B[a]P–DNA adduct levels were 56 ± 15/108 nucleotides (median ± SE) in adenomas versus 89 ± 19/108 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.
Abbreviations: AhR, aryl hydrocarbon receptor; APC, adenomatous polyposis coli; B[a]P, benzo[a]pyrene; BPDE, benzo[a]pyrene 7,8-diol-9,10-epoxide; CYP, cytochrome P450; FAP, familial adenomatous polyposis; GST, glutathione S-transferase; HNPCC, hereditary nonpolyposis colorectal cancer; Min, multiple intestinal neoplasia; MIS, microsatellite instability.
2 To whom correspondence should be addressed Email: f.c.campbell{at}newcastle.ac.uk
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