Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk

Abstract

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...

Drug‐Metabolizing Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition

“…CYP2C9 messenger RNA (mRNA) was detected in the prostate, but mRNA for CYP2C8, CYP2C18, and CYP2C19 were absent (Klose et al, 1999). In contrast to the report of Yokose et al, CYP3A5 has been detected in the prostate (Agundez et al, 1998;Yamakoshi et al, 1999;Finnström et al, 2001). CYP1A, CYP2C, CYP2D, and CYP3A are important catalysts of drug biotransformation.…”

“…The polymorphically distributed CYP2D6 has also been detected in the prostate (Agundez et al, 1998). Activity (N-demethylation of dextromethorphan) was approximately 10% of that in liver.…”

“…As discussed in the section on metabolism of prostate drugs, these CYPs are involved in their biotransformation. Indeed, Agundez et al (1998) reported that the Michaelis constants (K m s) for CYP3A substrate oxidation in the prostate were similar to those in liver, notwithstanding the much lower V max values, reflecting the lower level of protein expression.…”

Heterocyclic amines and genotype of N-acetyltransferases as risk factors for prostate cancer

“…Human prostate epithelial cells express NATs and they are capable of activating heterocyclic amines. 16,17 It has been reported that there is an association between NAT genotypes and PCa. [18][19][20] We have reported an association of NAT genotypes with PCa in patients who also have bladder cancer.…”

Genetic Variants of CYP2D6 Gene and Cancer Risk: A HuGE Systematic Review and Meta-analysis

“…According to the inclusion criteria, 43 studies (Agúndez et al, 1994;Wundrack et al, 1994;Agúndez et al, 1996;Ladona et al1996;Legrand et al, 1996;London et al, 1997;Agúndez et al, 1998;Febbo et al, 1998; González et al, 1998; Hu et Shaw et al, 1998;Krajinovic et al, 1999;Lemos et al, 1999;Topić et al, 2000;Butler et al, 2001;Liu et al, 2002;Sobti et al, 2003;Chen et al, 2004;Fukatsu et al, 2004;Li et al, 2004;Gajecka et al, 2005;Gomes et al, 2005;Guo et al, 2005;Liang et al, 2005;Mochizuki et al, 2005;Sobti et al, 2005;Aydin-Sayitoglu et al, 2006;Bonanni et al, 2006;Li et al, 2006;Lemos et al, 2007;Chen et al, 2008;Khedhaier et al, 2008;Majumdar et al, 2008;Ouerhani et al, 2008 ;Torresan et al, 2008;Yan et al, 2008;Altayli et al, 2009;Gutman et al, 2009;Lim et al, 2011;Luo et al, 2011;Zhou et al, 2011) appeared to have met the inclusion criteria and were subjected to further examination. The flow chart of study selection is shown...…”