Summary The role of two common polymorphisms of enzymes involved in the metabolism of drugs and carcinogens was studied in relation to prostate cancer. The gene encoding one of these enzymes (NAT2) is located in an area where frequent allelic loss occurs in prostate cancer. Mutations at the genes CYP2D6 and NAT2 were analysed by allele-specific polymerase chain reaction and restriction mapping in DNA from 94 subjects with prostate cancer and 160 male healthy control subjects. Eleven prostate specimens were analysed for genotype and enzymatic activities NAT2, CYP2D6 and CYP3A by using the enzyme-specific substrates sulphamethazine and dextromethorphan. Enzyme activities with substrate specificities corresponding to NAT2, CYP2D6 and CYP3A are present in human prostate tissue, with mean ± s.d. activities of 4.8 ± 4.4 pmol min-' mg-' protein, 156 ± 91 and 112 ± 72 nmol min-' mg-' protein respectively. The Km, values for the prostate CYP2D6 and CYP3A enzyme activities corresponded to that of liver CYP2D6 and CYP3A activities, and the CYP2D6 enzyme activity is related to the CYP2D6 genotype. The N-acetyftransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyttransferase activity that is independent of the regulation of the NAT2 gene. are expressed in human prostate tissue. The presence of carcinogen-metabolizing enzymes in human prostate with a high interindividual variability may be involved in the regulation of local levels of carcinogens and mutagens and may underie interindividual differences in cancer susceptibility. 1362 JAG Agundez et al due to a strong local effect on the actixation or deactivation of carcinogens in situ. For instance. it has been shovA-n that N-acetvltransferase polx morphism play s a relevant role in the formation of 2-aminofluorene-DNA adducts in tumour target organs (Feng et al. 1996). In an attempt to elucidate the events that occur as previous steps to prostate carcinogenesis. x e hax e studied A hether the poix-morphic enzymes CYP2D6 and NAT2 are actix ely expressed in human prostate tissue. as well as the impact of such genetic polx morphisms in prostate cancer susceptibility. In order to ex aluate w-hether allelic loss of these genes occurs in adenomatous prostate tissue. the occurrence of allelic losses at the CYP2D and .VA72 gene loci in prostate tissues was also studied. If the CYP2D6 enzyrme is functionally expressed in prostate. allelic loss of CYP2D6 could cause changes in local enzyme activity. modifving the local metabolism of carcinooens and mutarens. To our know-ledge. no studies involving allelic loss of the polymorphic gene CYP2D6 haxe been performed. This is also the first study inxolxing allelic loss of the NVA72 gene in prostate. Indeed only one study involvin2 allelic loss of NAT2 has been published. and it was performed in colon cancer (Hubbard et al. 1997). Keywords METHODS Patients and controlsAll the subjects included in this studx were unrelated v hite Spanish men. samples from t...

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Background/Aims: Autosomal dominant Alport syndrome represents 5% of all Alport syndrome cases. This entity presents a different clinical expression from the recessive inheritance pattern and the X chromosome-linked pattern, because it is mild and it shows a late onset, which in many cases even goes unnoticed. Methods: We carried out a descriptive observational and retrospective clinical study on 19 patients from 5 families with a clinical diagnosis of autosomal dominant Alport Syndrome, and we analyzed the expression of the symptoms in the different families, comparing the results with what has been described in the literature. Results: Renal involvement appeared at a young age, with a progression towards end-stage chronic kidney disease at a median age of 31 years (20.5-36.5). Hearing involvement also appeared in early stages, at a median age of 28.5 years (7.5-62.5). Also, we observed ocular lenticonus-like injuries, which until now have only been described in other inheritance patterns. Conclusions: Our results suggest that dominant patterns are accompanied by a severe clinical expression that can be superimposed to the recessive and X chromosome-linked patterns, contrary to what has been classically stated. The high phenotypic variability observed in the families lead to the fact that many cases go unnoticed and the severest cases are erroneously diagnosed as recessive, which means that the real prevalence of dominant forms is probably higher than the current 5%.

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Tuberous sclerosis is rarely associated with autosomal dominant polycystic kidney disease in the so-called tuberous sclerosis complex. This association leads to an increased frequency of end-stage renal disease. We present a patient suffering from both syndromes, who received a renal graft and anticalcineurinic drugs as immunosuppressive agents. Progressive titration of the drug was necessary in order to attain the effective doses due to the enzymatic induction caused by concomitant treatment with antiepileptic drugs. These high doses resulted in nephrotoxicity. Immunosuppressor treatment was switched to rapamycin, whereby an improvement in renal function and other signs of tuberous sclerosis and polycystic kidney disease was observed. This case report highlights both the efficacy and safety of rapamycin as an immunosuppressor treatment and its capacity for controlling other symptoms of these genetic-related disorders.