Showing papers by "Julio Benítez published in 1996"
TL;DR: It is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones, and partly responsible for the variations in haloperidol disposition between races.
Abstract: Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. The metabolism of several important drugs (e.g. haloperidol) cosegregates with that of debrisoquine. Thus, interethnic differences in debrisoquine hydroxylation polymorphism (CYP2D6) might be partly responsible for the variation in haloperidol disposition between races. The influence of tobacco, ethanol, caffeine, gender, and oral contraceptive use on the debrisoquine metabolic ratio (MR) has been analyzed in 633 Spanish healthy volunteers. MR was also determined in panels of healthy volunteers. 18 smokers were studied during a tobacco abstinence period, and 31 women three times during the same menstrual cycle. Among EMs, debrisoquine MR was significantly (P < 0.05) lower during smoking cessation (mean antilog +/- SD, 0.48 +/- 0.29) compared to a smoking period (0.61 +/- 0.23). During the lutheal phase of the menstrual cycle, debrisoquine MR was also significantly (P < 0.01) lower (0.33 +/- 0.41) compared to the ovulatory-phase (0.41 +/- 0.34) and the phase before ovulation (0.44 +/- 0.36). Among EMs, it is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones. The clinical relevance of these findings remains unclear.
83 citations
TL;DR: 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% of subjects with two rapid genes, and about 94% subjects with one rapid gene.
Abstract: 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.
71 citations
TL;DR: 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) and the additional determination of alleles of the cytochrome P450 2D6 (CYP2D6) gene in the same subjects confirmed the previous findings that subjects with two active CYP2D 6 genes are at increased risk of developing H CC.
Abstract: 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.
63 citations
TL;DR: 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.
Abstract: 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.
53 citations
TL;DR: 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.
Abstract: 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: 0055 in patients, 0025 in controls (non-significant difference) and 0108 in the 37 patients who had drunk more than 50 g of ethanol/day (p = 00035, odds ratio versus controls: 467; 95% confidence limits 157 to 1381) 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
23 citations
TL;DR: The findings do not provide a genetic basis for any association of NIDDM and NAT2 polymorphism, suggesting that any excess of subjects with the rapid acetylator phenotype among patients with NID DM should be secondary to the disease or concomitant drug therapy.
Abstract: The arylamine N-acetyltransferase (NAT2) polymorphism has been related to the risk of developing non-insulin-dependent diabetes mellitus (NIDDM). Several studies suggested an excess of rapid acetylators among NIDDM patients. This may be explained by an increased risk to develop NIDDM among subjects with the rapid acetylator capacity, or by changes in the acetylator status due to the disease or drug therapy. In order to elucidate this controversial topic, we have studied by a mutation-specific polymerase chain amplification (PCR) method the occurrence of seven point mutations at the coding region of the NAT2 gene in genomic DNA from 111 patients with NIDDM and 217 healthy controls. In addition, we have studied by the combined use of PCR and restriction fragment length polymorphism the occurrence of seven allelic variants of the CYP2D6 gene in the same subjects. In contrast to previous phenotyping studies, no relationship was found between NAT2 polymorphism and NIDDM or its complications such as nephropathy or neuropathy. The CYP2D6 genotype was similar between cases and controls. Our findings do not provide a genetic basis for any association of NIDDM and NAT2 polymorphism, suggesting that any excess of subjects with the rapid acetylator phenotype among patients with NIDDM should be secondary to the disease or concomitant drug therapy.
18 citations
8 citations
Journal Article•
TL;DR: It is concluded that the acetylator status is not a major factor in lung cancer risk, however the presence of the 341C + 481T + 803G and the 590A alleles of the polymorphic NAT2 gene may be a secondary risk factor for the development of lung cancer.
4 citations
TL;DR: In spite of its induction of monoamine depletion in intact animals, Ovariectomy partially prevented MPTP-induced depletion of monoamines in the surviving rats, suggesting that changes in metabolic rates of debrisoquine induced by ovariectomy produce resistance to MPTP in 'dark-adapted' rats.