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Association of low CYP3A activity with p 53 mutation and CYP2D6 activity with Rb mutation in human ...

Association of low CYP3A activity with p 53 mutation and CYP2D6 activity with Rb mutation in... p53 and Rbgene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rbmutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivoCYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rbprotein expression was evaluated with antibody PMG3–245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P< 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rbprotein (P< 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P< 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P< 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rbmutations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Carcinogenesis Oxford University Press

Association of low CYP3A activity with p 53 mutation and CYP2D6 activity with Rb mutation in human ...

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References (39)

Publisher
Oxford University Press
Copyright
© Oxford University Press
ISSN
0143-3334
eISSN
1460-2180
DOI
10.1093/carcin/17.5.1057
Publisher site
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Abstract

p53 and Rbgene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rbmutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivoCYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rbprotein expression was evaluated with antibody PMG3–245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P< 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rbprotein (P< 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P< 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P< 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rbmutations.

Journal

Carcinogenesis – Oxford University Press

Published: May 1, 1996

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