| 1. |
|
|
| 2. |
- Wadelius, Mia, et al.
(författare)
-
Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer
- 1999
-
Ingår i: Pharmacogenetics. - 0960-314X .- 1473-561X. ; 9:3, s. 333-40
-
Tidskriftsartikel (refereegranskat)abstract
- The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance.
|
|
| 3. |
- Wadelius, Mia, et al.
(författare)
-
Prostate cancer associated with CYP17 genotype
- 1999
-
Ingår i: Pharmacogenetics. - 0960-314X .- 1473-561X. ; 9:5, s. 635-9
-
Tidskriftsartikel (refereegranskat)abstract
- Androgens play an important role in the development of prostate cancer. Androgen regulating genes that show allelic variation may be susceptibility factors for the disease. One of these genes, CYP17, encodes the cytochrome P450c17alpha enzyme. It catalyses steroid 17alpha-hydroxylase/17,20 lyase activities at key points in testosterone biosynthesis. We investigated the association between a polymorphism in the CYP17 gene and prostate cancer in a population-based case-control study. All individuals studied were Caucasians born in Sweden, 178 were consecutive clinical prostate cancer patients, and 160 were age-matched control individuals randomly selected from the same catchment area. DNA was extracted from blood samples. A CYP17 gene fragment was amplified by polymerase chain reaction. The MspA1I restriction enzyme, which recognizes the base pair substitution, was used to identify the allelic variants CYP17A1 and CYP17A2. Significantly more men homozygous for the CYP17A1 allele were found among prostate cancer patients compared with control individuals; odds ratio 1.61 (95% confidence interval 1.02; 2.53), P = 0.04. According to a preliminary report, the CYP17A1/A1 genotype leads to higher circulating androgen levels, possibly by encoding for a more active androgen synthesizing CYP17 enzyme. Consequently, the CYP17A1/A1 genotype, which was found in a higher frequency among prostate cancer patients, may prove to be one of the important susceptibility factors for prostate cancer. If verified, this genotype is likely to convey a larger risk on a population basis, than the rare hereditary prostate cancer genes do.
|
|
| 4. |
- Smith, C.A., et al.
(författare)
-
A simplified assay for the arylamine N-acetyltransferase 2 polymorphism validated by phenotyping with isoniazid
- 1997
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 34:9, s. 758-60
-
Tidskriftsartikel (refereegranskat)abstract
- Human arylamine N-acetyltransferase (NAT) activity is determined by two distinct genes, NAT1 and NAT2, and the classical acetylation polymorphism in NAT2 has been associated with a variety of disorders, including lupus erythematosus and arylamine induced cancers. Over 50% of the white population exhibit a slow acetylator phenotype. The genetic basis of the defect has been identified and several DNA based assays are available for genotyping studies. We present here a simplified, rapid PCR based assay for the identification of the major slow acetylator genotypes and validate it using isoniazid as probe drug. This assay was 100% predictive of phenotype. The three genotypes (homozygous mutated, heterozygous, and homozygous rapid) corresponded to a trimodal distribution of Ac-INH/INH metabolic ratios (slow, intermediate, and rapid) without overlapping.
|
|
| 5. |
- Wadelius, Mia, et al.
(författare)
-
Induction of CYP2D6 in pregnancy
- 1997
-
Ingår i: Clinical Pharmacology and Therapeutics. - 0009-9236 .- 1532-6535. ; 62:4, s. 400-7
-
Tidskriftsartikel (refereegranskat)abstract
- Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.
|
|
| 6. |
- Wadelius, Mia
(författare)
-
Pharmacogenetic analysis in sickness and in health - for better or for worse
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An individual's pharmacogenetic constitution may predict response to drugs, hormones and toxins, and might be a susceptibility factor for disease. Pharmacogenetic diversity is especially pronounced for drug metabolising enzymes. In these studies the following five enzymes have been genotyped: N-acetyltransferase 2 (NAT2), sparteine/debrisoquine hydroxylase (CYP2D6), mephenytoin hydroxylase (CYP2C19), steroid 17α-hydroxylase (CYP17), and glutathione S-transferase P1 (GSTP1).A simplified method for genotyping NAT2 was verified by phenotyping with isoniazid. All phenotypes: slow, intermediate and fast acetylators were correctly identified by genotyping. This method was used to genotype control subjects and patients who reacted to sulphasalazine with agranulocytosis. The incidence of slow acetylation was equal in agranulocytosis patients and population-based controls. However, the incidence of slowacetylation was significantly reduced in patients who tolerated sulphasalazine compared with both agranulocytosis patients and population-based controls.Different genotypes of the enzymes NAT2, CYP2D6, CYP2C19, GSTP1 and CYP17 were studied as possible susceptibility factors for prostate cancer in a case-control study. No association was found between prostate cancer and NAT2, CYP2D6, CYP2C19 orGSTP1 genotypes. A certain genotype of CYP17, encoding a key enzyme in testosterone synthesis, was associated with prostate cancer, a finding that warrants further studies. CYP2D6 is not considered to be an inducible enzyme, but phenotyping of pregnant women showed that CYP2D6 activity is increased during pregnancy. This may be caused by enzyme induction, suggesting possible impact on drug treatment during pregnancy. In the future, as more pharmacogenetic information becomes available, predicting individual drug responses will become an essential part of therapy.
|
|
