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The ability to 4-hydroxylate debrisoquine is related to recurrence of bladder cancer
C M Fleming1, A Kaisary, G R Wilkinson
1Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Abstract:
Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Cytochrome P450 enzyme activity, specifically debrisoquine metabolism, is linked to bladder cancer recurrence. Higher debrisoquine recovery ratios indicate an increased risk of tumor recurrence in bladder cancer patients.
Area of Science:
- Pharmacogenomics
- Oncology
- Metabolism
Background:
- Cytochrome P450 enzymes are crucial for metabolizing environmental procarcinogens.
- Understanding metabolic enzyme activity can help predict cancer recurrence risk.
Purpose of the Study:
- To investigate the association between in vivo metabolic enzyme activities and bladder cancer recurrence.
- To assess the predictive value of specific P450 enzyme probes for tumor recurrence.
Main Methods:
- Utilized debrisoquine, mephenytoin, and dapsone as in vivo probes for P4502D6, P4502C9, P4503A4, and N-acetyltransferase activities.
- Measured urinary recovery ratios and plasma metabolite levels in 95 bladder cancer patients post-surgery.
- Followed patients for 3 years to monitor tumor recurrence.
Main Results:
- A significantly higher debrisoquine recovery ratio was observed in patients who experienced tumor recurrence compared to those who remained disease-free.
- This association remained significant even within the subgroup of patients with non-aggressive (G-I and G-II) histopathology.
Conclusions:
- Debrisoquine metabolism activity, reflecting P4502D6 function, is a potential biomarker for predicting bladder cancer recurrence.
- Further research into pharmacogenetic markers could improve personalized risk assessment for bladder cancer patients.