Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug metabolizing enzymes are of paramount importance in drug detoxification as well as chemical mutagenesis, carcinogenesis and toxicity via metabolic activation. Thus genetically determined differences in the activity of these enzymes can influence individual susceptibility to adverse drug reactions, drug induced diseases and certain types of chemically induced cancers. The genetic polymorphisms of three human drug metabolizing enzymes, namely N-acetyltransferase and two cytochrome P-450 isozymes (P-4502D6: debrisoquine/sparteine polymorphism, P-4502C8-10: mephenytoin polymorphism) have been firmly established. Based on the metabolic handling of certain probe drugs, the population can be divided into two phenotypes: the rapid acetylator/extensive metabolizer and slow acetylator/poor metabolizer. These polymorphisms have provided useful tools to study the relationship between genetically determined differences in the activity of drug metabolizing enzymes and the risk for adverse drug reactions and certain types of chemically-induced diseases and cancers. With regard to the susceptibility of the two phenotypes, drug mediated toxicity for the following scenarios can be anticipated. (1) The toxicity of the drug is caused by the parent compound and the elimination of the drug proceeds exclusively via the polymorphic enzyme. No alternate pathways of biotransformation are available. Thus the slow acetylator/poor metabolizer phenotype will be more prone to such a type of toxicity since, at the same level of exposure, this phenotype will accumulate the drug as a result of impaired metabolism (e.g. isoniazid polyneuropathy, perhexiline polyneuropathy, pesticide induced Parkinsons disease). (2) The polymorphic pathway is a major route of detoxification. Impairment of this pathway shifts the metabolism to an alternate pathway via which a reactive intermediate is being formed. In such a situation the slow acetylator/poor metabolizer phenotype constitutes a major risk factor for toxicity (e.g. isoniazid hepatotoxicity). (3) The toxicity is mediated by a reactive intermediate generated by a polymorphic enzyme. Hence extensive metabolizers are at a much higher risk than poor metabolizers to develop toxicity or cancer (e.g. bronchial carcinoma in smokers, not chemically induced aggressive bladder cancer).
 ...
PMID:Genetically determined differences in drug metabolism as a risk factor in drug toxicity. 147 Nov 65

Genetically determined polymorphisms of N-acetylation and oxidative capacity have been studied using dapsone and metoprolol in 51 Japanese patients with spontaneous bladder cancer and 203 healthy control subjects. The results for N-acetylation pharmacogenetics were against the initial expectation that there would be a preponderance of slow acetylators in the cancer group, as 3 such patients (5.9%) were found as compared to 13 (6.4%) in the healthy group. There was no poor metabolizer (PM) of metoprolol in the cancer group, whereas in the healthy group one (0.5%) was a PM. There were no significant differences between the groups in the frequency of slow acetylator and poor oxidiser phenotypes, or in the frequency distribution profiles of acetylation (monoacetyldapsone/dapsone) and oxidative metabolic ratio (log metoprolol/alpha-hydroxymetoprolol). The results indicate that neither N-acetylation nor the debrisoquine/sparteine-type oxidative phenotype and/or capacity represent a genetic predisposition to spontaneous bladder carcinogenesis in Japanese patients. In the normal Japanese population there is a great predominance of rapid acetylators and extensive oxidisers.
 ...
PMID:Genetically determined N-acetylation and oxidation capacities in Japanese patients with non-occupational urinary bladder cancer. 261 54

The clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow - and possibly intermediate - acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes. Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable. If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy. Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype - especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fa
 ...
PMID:Genetically determined variability in acetylation and oxidation. Therapeutic implications. 285 77

The results of our study revealed a predominance of the percentage of extensive metabolizers (EM) of sparteine (94.8%) among 58 patients with non-occupational urinary bladder cancer in comparison with the percentage of extensive metabolizers (91.2%) in healthy persons; the difference being not statistically significant. However, among ultrarapid (EM) oxidators with the metabolic ratio (MR) < 0.5 the difference in the MR frequency distribution between 15 patients with bladder cancer (25.9%) and 18 healthy persons (11.25%) was statistically significant. Therefore, our studies provide some evidence of a possible relationship between the EM sparteine oxidation phenotype and the susceptibility to non-occupational bladder cancer. Not statistically significant slight prevalence of the percentage of slow acetylators (SA) (53.1%) among 32 urinary bladder cancer patients in comparison with the percentage of SA (49%) among 45 healthy persons may confirm the conclusion that a slow acetylator phenotype is not associated with the increased risk of the development of non-occupational urinary bladder cancer.
 ...
PMID:Genetically determined sparteine oxidation and sulfadimidine acetylation polymorphism in patients with non-occupational urinary bladder cancer. 766 80

Cytochrome P450 CYP2D6 polymorphism is an autosomal recessive trait leading to impaired sparteine/ debrisoquine metabolism in 5-10% of the Caucasian population. Previous studies have associated affected individuals (poor metabolizers = PM) with susceptibility to bladder cancer and various forms of leukemia. In many other cancer forms, the data remain contradictory. A PCR assay allows the convenient screening of about 90% of known mutations resulting in the PM phenotype. Since in patients with neurofibromatosis type 2, we had observed a significantly increased rate of CYP2D6 mutations leading to PM and apparently predisposing for NF2, we extended our investigation to tumor and peripheral blood samples obtained from NF1 patients. Although the number of cases investigated remains low, the study indicated that during tumor formation no changes occurred at the mutational hot spot within the CYP2D6 sequence. Moreover, no loss of heterozygosity was notable. However, the frequency of the mutated allele in the NF1 individuals is comparable to that of neurofibromatosis type 2 and above that observed in breast and colon cancer, or meningiomas.
 ...
PMID:Debrisoquine hydroxylase gene polymorphism in neurofibromatosis type 1. 949 60