[Enzymatic polymorphisms and pulmonary cancer].
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Cytochrome P-450 Enzyme System↗
Biomedical subjects
J M Ladero
Publications and source records attributed to J M Ladero.
Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk.
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(-1) mg(-1) protein, 156+/-91 and 112+/-72 nmol min(-1) mg(-1) 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-acetyltransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyltransferase 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 underlie interindividual differences in cancer susceptibility.
Aged↗
Acarbose-induced acute hepatitis.
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Acarbose↗
Hepatitis G virus infection in Spanish patients with hepatocellular carcinoma.
AIMS/BACKGROUND: To establish the rate of infection with a newly discovered Flaviviridae family member hepatitis G virus (HGV) -- in Spanish patients with hepatocellular carcinoma (HCC), chronic alcoholic liver disease (CALD) with cirrhosis, or hepatitis C virus (HCV)-induced chronic hepatitis (CH). METHODS: The presence of HGV-RNA was assessed in sera of 117 patients divided in three groups: group 1: 40 patients with HCC (35 men, mean age 62.7 years, SD 10.9 years); group 2: 41 patients with chronic alcoholic liver disease (CALD) (36 men, mean age 52.5 years, SD 9.8 years); group 3: 36 patients with HCV-induced CH (27 men, mean age 35.8 years, SD 8.5 years). Serum samples were tested for HGV-RNA by specific reverse transcriptase-polymerase chain reaction (RT-PCR). Serological markers of hepatitis B virus (HBV) and HCV were investigated in all patients and were negative in CALD patients, as a prerequisite for their inclusion in the study. All patients in group 1 were also tested for HBV-DNA. RESULTS: Rates of HGV-RNA positivity were, respectively, 47%, 10% and 28% in groups 1, 2 and 3. Differences were significant between groups 1 and 2 (p=0.00017) and groups 2 and 3 (p= 0.042), but not between groups 1 and 3 (p=0.079). CONCLUSIONS: HGV infection is common in HCC patients, but usually in association with HCV, indicating that both agents share common routes of infection. HGV was the only hepatitis virus detected in 12% of HCC patients, but its possible role in the pathogenesis of HCC remains unclear.
Adult↗
Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson's disease.
OBJECTIVE: To determine the frequency and the linkage distribution of seven mutations at the polymorphic gene coding for the arylamine N-acetyl transferase (NAT2; EC 2.3.1.5) in 121 unrelated patients with sporadic PD and in 121 unrelated healthy volunteers. METHODS: The study was performed with mutation-specific PCR using genomic DNA obtained from blood of the probands. RESULTS: Comparison of the NAT2 genotypes of the overall PD patients and control subjects did not indicate statistically significant differences. However, patients with early-onset PD (onset before the age of 50 years, n=37) showed a higher frequency of slow-acetylation genotypes (78.4% patients) compared with both healthy control subjects (55.4%) and with late-onset (onset after 51 years of age, n=84) PD patients (54.8%). Such a difference was statistically significant (p < 0.015) and was the result of a homogeneous increase in the frequency of slow-acetylation alleles. All subgroups analyzed in the study were in Hardy-Weinberg equilibrium for mutations at the NAT2 gene. CONCLUSIONS: Slow-acetylation-mutated alleles may be considered low-penetrance genes in early-onset PD pathogenesis, with a relative risk ratio for individuals with slow-acetylation genotype of 2.92 (95% CI, 1.26 to 6.78). This study provides evidence for the interaction of genetic and environmental factors in the etiology of sporadic PD.
Adult↗
CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians.
BACKGROUND: enzymatic polymorphisms affecting the metabolic disposition of xenobiotics may modulate the rate of activation or deactivation of carcinogens and other toxic environmental chemicals. Hence, these polymorphisms may influence the risk of suffering some types of cancer and other degenerative diseases that are incompatible with extreme longevity. AIMS: to establish the distribution of three well known enzymatic polymorphisms that affect the CYP2D6, NAT-2 and CYP2E1 genes and the activity of their enzymatic gene products, involved in the disposition of many xenobiotics, in a group of nonagenarians and in much younger controls. PATIENTS: the three genotypes were determined in 41 nonagenarians (10 males, mean age 92.2 years, range 90-98) free of known malignancies or neurodegenerative diseases. The control groups comprised 217 healthy volunteers (128 males, mean age 36.3 years; SD, 12.7) for the CYP2D6 and NAT2 genotypes and 137 (116 males, mean age 32 years; SD, 18.8) for the CYP2E1 genotype. METHODS: after extraction of DNA from white blood cells, polymerase chain reaction and restriction fragment polymorphism methods were used to identify the allelic variants of the three genotypes. RESULTS: we found no qualitative or quantitative difference in the mutations underlying the three genetic polymorphisms studied, nor in the expected enzymatic phenotypes. Instead, a close parallelism exists between advanced age and younger groups. CONCLUSION: longevity does not seem to be related to any special configuration of these three polymorphic traits. Comparisons with younger controls may be adequate when studying the distribution of these polymorphisms in diseases affecting old people. No genetically determined differences in the activation of drugs metabolized by these enzymes are to be expected in very old people.
Aged↗
CYP2A6 gene polymorphism and risk of liver cancer and cirrhosis.
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Adult↗
CYP2D6 polymorphism is not associated with essential tremor.
Recent reports have shown an association between cytochrome P450IID6 (CYP2D6) polymorphism and Parkinson's disease. We investigated the association between this polymorphism and the risk for developing essential tremor (ET). Leukocytic DNA from 91 unrelated ET patients and a control group of 258 unrelated healthy individuals was studied for the occurrence of eight different CYP2D6 allelic variants by using allele-specific PCR amplification Xbal and EcoRI-RFLP's analyses. The prevalence for these allelic variants in the ET and control groups were, respectively: CYP2D6*1 76.9 and 78.7%, CYP2D6*2 0.5 and 0.2%, CYP2D6*3 0 and 1%, CYP2D6*4 12.1 and 12.2%, CYP2D6*5 1.6 and 1.7%, CYP2D6*9 4.4 and 2.9%, CYP2D6*2x2 4.4 and 3.2%. The prevalence of subjects with absent CYP2D6 activity (those carrying two defect genes) was 1.1 and 3.1% in ET and control groups, respectively. Both groups studied were in Hardy-Weinberg equilibrium. These results indicate that mutations at the CYP2D6 gene do not seem to be a major factor in determining susceptibility to ET, and reinforces the view that ET and parkinsonism are distinct conditions.
Adolescent↗
[Empathy: the quintessence in medicine].
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Empathy↗
CYP2D6 genotypes in Spanish women with breast cancer.
Wild type and three mutated alleles of the polymorphic CYP2D6 gene were studied in genomic DNA samples from 187 women with breast carcinoma and 151 healthy women by a mutation-specific polymerase chain reaction. The prevalence of the enzyme-inactivating CYP2D6(B) allele was higher among patients (18.2%) than in controls (11.6%; OR = 1.7; 95% c.i. = 1.14-3.13; P = 0.018). This excess was more marked in postmenopausal patients (19.8%, P = 0.0086) and in patients with non-ductal infiltrating carcinomas (25.8%, P = 0.003). The percentage of carriers of only one active gene (heterozygote extensive metabolizers) was higher in patients (31% vs. 19.9%; OR = 1.81; 95% c.i. = 1.06-3.11; P = 0.02). The CYP2D6(B)-carrier state may be related to a greater risk of breast cancer in women.
Adult↗
The role of sonography in the early diagnosis of biliopancreatic Ascaris infestation.
Acute pancreatitis due to ascaris lumbricoides infestation is extraordinarily uncommon in Europe. The diagnosis can be difficult because of the low index of suspicion in our area, and this may lead to death. The case of a Columbian patient living in Spain who developed an acute pancreatitis is discussed. He had no history of alcohol abuse, gallstones, or drug abuse. The sonography showed a longitudinal structure with inner parallel linear bands and undulant movements inside the gallbladder and a hypoechogenic pancreas. These features are compatible with acute pancreatitis secondary to Ascaris lumbricoides infestation. The patient was treated with mebendazole and his evolution was excellent. Sonography was useful as an assessment modality during follow-up. We conclude that Ascaris lumbricoides should be recalled as a rare cause of acute pancreatitis in Western countries. Sonography allows early diagnosis and prompt treatment.
Acute Disease↗
Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers.
The arylamine N-acetyltransferase (NAT2) is a polymorphic enzyme which is expressed in the liver in a genotype-determined manner. NAT2 is involved in activation and inactivation of carcinogens through N-acetylation. We studied the role of this polymorphism in the development of hepatocellular carcinoma (HCC). One hundred consecutive patients diagnosed for HCC and 258 healthy volunteers were studied for NAT2 genotype. The occurrence of seven enzyme-inactivating and silent point mutations in the coding region of the NAT2 gene was studied by mutation-specific PCR amplification. An excess of subjects homozygous for NAT2 loss of function alleles was observed among patients with HCC (68% vs 53.9% controls). The relationship between the slow acetylator NAT2 genotype and HCC risk is more pronounced in patients lacking serum HBV and HCV markers. The additional determination of alleles of the cytochrome P450 2D6 (CYP2D6) gene in the same subjects confirmed our previous findings that subjects with two active CYP2D6 genes are at increased risk of developing HCC. The genetic polymorphism of NAT2 is a relevant factor in the risk for developing HCC (inverse odds ratio slow vs rapid = 1.8; 95% CI 1.1-3.0). The inverse odds ratio for subjects with two risk genotypes (two defect NAT2 genes and two or more active CYP2D6 genes) is 2.6 (95% CI 1.6-4.4) for all patients with HCC, and 5.6 (95% CI 1.4-33.3) for patients without serum viral markers.
Adult↗
RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma.
BACKGROUND: CYP2E1, the coding gene for the ethanol inducible cytochrome P4502E1, is polymorphic at the RsaI restriction site in the 5' flanking region. The mutant allele c2 has a higher transcriptional activity than the wild-type gene c1. P4502E1 catalyses the activation of several environmental carcinogens at a rate that is increased, if only moderately, by longterm ethanol intake. AIMS: To establish the distribution of CYP2E1 RsaI polymorphism in patients with hepatocellular carcinoma and to evaluate its possible role in the multifactorial pathogenesis of this tumour. SUBJECTS: 101 (84 males) patients with hepatocellular carcinoma and 178 (128 males) healthy controls of the same ethnic (white) and Spanish origin. METHODS: After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease RsaI. RESULTS: Homozygous c1c1: 90 patients and 169 controls; heterozygous c1c2: 11 and 9; homozygous c2c2: none (non-significant difference). C2 allele frequencies: 0.055 in patients, 0.025 in controls (non-significant difference) and 0.108 in the 37 patients who had drunk more than 50 g of ethanol/day (p = 0.0035, odds ratio versus controls: 4.67; 95% confidence limits 1.57 to 13.81). CONCLUSION: The carrier state of one copy of the c2 CYP2E1 gene increases the risk of hepatoma in previously regular ethanol users with chronic liver disease.
Adult↗
Identification and prevalence study of 17 allelic variants of the human NAT2 gene in a white population.
The prevalence and distribution of seven point mutations at the coding region of the highly polymorphic NAT2 gene were studied in 1008 chromosomes from healthy Spanish subjects. Most of the genes studied (78.4%) had one or more mutations, distributed in seventeen allelic variants of the NAT2 gene. Three alleles were present at high frequencies, namely NAT2*5B (41.6%), NAT2*6A (23.6%) and NAT2*4 (21.6%). The frequencies for the rest of alleles were: NAT2*12A (2.5%), NAT2*6B (2.0%), NAT2*13 (1.9%), NAT2*5A (1.5%), NAT2*7B (1.2%), NAT2*12C (1.0%), NAT2*5C (0.8%), NAT2*14C (0.8%), NAT2*14A (0.6%), NAT2*5D (0.3%), NAT2*12B (0.2%), and NAT2*14D (0.1%). In addition, we identified two new allelic variants with mutations at 191A + 341C + 803G (0.1%) and 282T + 590A + 803G (0.3%) which to our knowledge are described here for the first time. No other combination of mutations was identified, including the previously described allelic variants NAT2*14B, NAT2*14E, NAT2*5E and NAT2*7A. The phenotype predictive capacity of simplified PCR tests including analyses for mutations at 341C and 590A, and more sophisticated tests analysing seven mutations revealed that, in the population studied, the analysis of these two mutations is enough to predict as rapid acetylators over 99.5% subjects with two rapid genes, and about 94% subjects with one rapid gene. Given a prevalence of poor acetylators of about 55% subjects, the simplified analysis would predict the phenotype in about 97.5% subjects.
Acetylation↗
CYP2D6 genes and risk of liver cancer.
We have studied by use of PCR and XbaI and EcoRI restriction-fragment-length polymorphism whether mutations at the polymorphic CYP2D6 (debrisoquine hydroxylase) gene locus are associated with liver cancer. The frequency of CYP2D6 genes containing inactivating mutations was lower among 75 liver cancer patients than 200 healthy controls, and 40 cirrhotic subjects that did not develop liver cancer (frequency for carriers of two or more functional genes was 95% vs 74% vs 78%, respectively). Subjects who were homozygous for functional CYP2D6 genes appear to be at higher risk of developing primary liver cancer (odds ratio 6.40 [95% Cl] 2.4-17.5).
Aged↗
Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population.
The occurrence of multiple copies of the CYP2D6 gene was investigated 217 white healthy Spaniards by the combined use of Xba I and Eco RI restriction fragment length polymorphism (RFLP) analyses. About 3.5% of the alleles yielded an 12.1 kb Eco RI-RFLP product in combination with the 42 kb Xba I-RFLP product, which is indicative of multiple CYP2D6. The prevalence of subjects carrying multiple CYP2D6 was 7%. The 12.1 kb Eco RI-RFLP product was highly associated (60%) with the presence of the genotype 29wt/42wt, as characterized by mutation-specific polymerase chain reaction and Xba I-RFLP analyses. Six subjects who had multiple CYP2D6 had other genotypes, namely, 44wt/42wt (four subjects), 29C/42wt (one subject), and one subject had a 12.1 kb product plus the CYP2D6C mutation associated with the 44 kb/42 kb genotype. All subjects identified as carrying multiple CYP2D6 had only two CYP2D6 copies in the same chromosome and were classified as carriers of the (CYP2D6L)2 allelic variant. Phenotyping with debrisoquin indicated an increase in the oxidative capacity as a function of the number of functional CYP2D6 genes. The metabolic ratio and the 95% confidence limits were as follows: subjects lacking functional genes, 48.8 (95% confidence limits, 14.4 to 79.3); subjects with one functional gene, 2.14 (95% confidence limits, 0.61 to 3.67); subjects with two functional genes, 1.5 (95% confidence limits, 0.88 to 2.14); and subjects with three functional genes, 0.33 (95% confidence limits, 0.22 to 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Frequency of CYP2D6 allelic variants in multiple sclerosis.
Recent reports have shown association between CYP2D6 polymorphism and neuronal degenerative diseases such as Parkinson's disease. We investigated the association between this polymorphism and the risk for developing multiple sclerosis (MS). Leucocyte DNA from 118 MS patients and a control group of 200 unrelated healthy individuals was studied for the occurrence of 8 different CYP2D6 allelic variants by using allele-specific PCR amplification, XbaI and EcoRI RFLP analyses. The frequencies for these allelic variants in the MS and control groups were, respectively: CYP2D6wt 75.0% and 79.3%, CYP2D6A 0.4% and 1.3%, CYP2D6B 11.4% and 12.0%, CYP2D6C 4.2% and 2.0%, CYP2D6D 3.0% and 2.3%, CYP2D6L 0.8% and 0.3%, CYP2D6L2 5.1% and 3.0%. The frequencies of subjects with high CYP2D6 activity (those carrying two or more functional genes) were 77.1% and 73.5% in MS and control groups. The frequencies of subjects with absent CYP2D6 activity (those lacking functional genes) were 3.4% and 4.5% in MS and control groups, respectively. These results indicate that mutations at the CYP2D6 gene do not seem to be a factor in determining susceptibility to MS.
Alleles↗
Debrisoquine oxidation polymorphism in patients with chronic inflammatory bowel disease.
Polymorphic hydroxylation of debrisoquine (DBQ) is a Mendelian genetic trait related to the risk of suffering some spontaneous disorders. To elucidate whether such a relation exists between this polymorphism and chronic inflammatory bowel disease (CIBD), 67 (39 males) patients with ulcerative colitis (UC), 52 (35 males) patients with Crohn's disease (CD) and 837 healthy controls (391 males) received 10 mg debrisoquine. DBQ and its metabolite, 4-OH-DBQ, were measured in urine to calculate metabolic ratio. Subjects with MR < 12.6 (log 10 MR < 1.1) were extensive metabolizers (EM) of DBQ, whereas those with MR < 12.6 were poor metabolizers (PM). Four UC (5.97%), 1 CD (1.92%) patients and 42 controls (5.03%) were PM of DBQ (nonsignificant difference). When analysing the EM subjects separately, log10 MR were lower in controls (mean = -0.295, SD 0.427, P = 0.0015)) and in Crohn's disease patients (man = -0.281, SD 0.495, P = 0.03) than in ulcerative colitis patients (mean = -0.085, SD = 0.495). There is no relationship between oxidative phenotype of DBQ and the risk for CIBD. Nevertheless, the EM phenotype includes both homo- and heterozygote genotypes for functioning alleles exerting a gene-dose effect that gives a higher oxidative capability to homozygote EMs, reflected in a lower MR value. Genotyping studies are needed to disclose whether heterozygote EMs are over-represented among UC patients and to identify any nonfunctioning allele possibly linked to the risk of developing this disease.
Adult↗