Polymorphic enzymes of xenobiotic metabolism as modulators of acquired P53 mutations in bladder cancer.
Occurrence or specific types of mutations found in oncogenes or tumor suppressor genes may partially be determined by activities of toxifying or detoxifying enzymes, such as glutathione S-transferases (GST) M1 and T1, arylamine N-acetyltransferase (NAT2), microsomal epoxide hydrolase, and the cytochrome P-450 enzymes 2D6, 1A1, 2A6, and 2E1. In an explorative observational study, 69 bladder cancer patients were analysed for acquired mutations in the p53 tumor suppressor gene. The same patients were studied for the polymorphic traits of xenobiotic metabolism given above which were characterized from blood cell DNA by molecular methods. In 20 patients, single point mutations in p53 were detected whereas five patients carried two mutations; thus in total 25 mutations were detected. Twelve of these were G:C-->A:T transitions, six were A:T-->G:C transitions and seven were transversions (three G:C-->T:A, two A:T-->T:A, one G:C-->C:G, and one A:T-->C:G). There was no correlation between the types of p53 mutations and lifetime smoking or occupational history. In correlation with xenobiotic metabolism, 86% of the seven transversion mutations were found in homozygously deficient individuals for GSTM1 compared to only 44% of GSTM1 deficiency in the carriers of the 18 transition mutations of p53 (p = 0.06). A similar trend was seen for NAT2: six of the seven carriers of transversion mutations had two slow NAT2 alleles. No apparent associations were seen for the other polymorphic traits which were studied. In conclusion, low or deficient activities of two conjugating enzymes of foreign compound metabolism, GSTM1 and NAT2, may influence types of acquired mutations in p53 in bladder cancer.
Brockmöller
J
J
Institute of Clinical Pharmacology, Universitätsklinikum Charité, Humboldt-University of Berlin, Germany.
Kaiser
R
R
Kerb
R
R
Cascorbi
I
I
Jaeger
V
V
Roots
I
I
D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000378:metabolism; D016158:Genes, p53; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics*; D015262:Xenobiotics / Q000378:metabolism*
D017931:DNA Primers; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases