Biomedical subjects

J A G Agúndez

Publications and source records attributed to J A G Agúndez.

5 recordsLinked to original sources

PubMed2006

Increased frequency of rapid acetylator genotypes in patients with brain astrocytoma and meningioma.

OBJECTIVES: The arylamine N-acetyltransferase (NAT2) is a polymorphic enzyme involved in deactivation and activation of carcinogens through N- and O-acetylation. We investigated the association between the genetic NAT2 polymorphism and brain tumors by analysis of genomic DNA from 71 brain tumor patients and 258 healthy controls. MATERIALS AND METHODS: Seven single nucleotide polymorphisms of the NAT2 gene were studied by using allele-specific polymerase chain reaction amplification. RESULTS: Ten different NAT2 allelic variants were identified in both patient and control groups. A higher number of individuals carrying functional NAT2 genes, and therefore with a rapid acetylation phenotype, was found in brain tumor patients vs healthy volunteers (OR 1.79, 95% CI 1.05-3.05; P < 0.05). This is observed either for patients suffering from meningioma or astrocytoma, and this is due to an increase of the wild-type NAT2*4 allelic variant frequency (OR 1.48, 95% CI 0.99-2.19), and a reduction of the commonest defective allelic variant NAT2*5B in the brain tumor patients, compared with healthy subjects (OR 0.54, 95% CI 0.37-0.80). CONCLUSIONS: This observation indicates that NAT2 could be considered as a low-penetrance gene for brain tumors, and that individuals carrying rapid acetylation alleles are at increased risk of developing brain tumors.

Adult↗

PubMed2004

Leflunomide-induced acute hepatitis.

Leflunomide, a new immunomodulatory agent, was prescribed to a 67-year-old female patient with rheumatoid arthritis. Fifteen days later she developed diarrhoea and elevated liver enzymes. A liver biopsy showed a pattern of acute hepatitis. The patient was homozygous for the rare CYP2C9*3 allele, which determines the slowest metabolic rate for CYP2C9 enzymatic activity, that is probably involved in the metabolism of leflunomide. Liver damage subsided in few weeks. This case illustrates the risk of hepatotoxicity by leflunomide and suggests that it is possibly related to CYP2C9 polymorphism.

Adjuvants, Immunologic↗

PubMed2002

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy.

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity+/-s.d. for colorectal cancer microsomes was 67.8+/-36.6 pmol min(-1) mg(-1). The K(m) of the tumoral enzyme (42+/-8 microM) is similar to that in healthy colorectal epithelium (36+/-8 microM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1+/-1.2 pmol min(-1) mg(-1). The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a K(I) value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs.

Aged↗

PubMed2002

N-acetyltransferase 2 polymorphism is not related to the risk of advanced alcoholic liver disease.

BACKGROUND: Ethanol abuse is the most prevalent cause of liver cirrhosis in Spain. Genetic polymorphisms affect the activity of the enzymes involved in ethanol metabolism and in processing the toxic by-products generated in the liver. N-acetyltransferase 2 (NAT2) is a polymorphic phase 2 enzyme not involved in these processes, but recent data suggest that the most prevalent slow acetylator genotype protects against the risk of advanced alcoholic liver disease (ALD). We have identified six single nucleotide polymorphisms (SNP) at the NAT2 gene locus in order to disclose whether such an association exists. METHODS: Genomic DNA from 95 ALD patients (15 with superimposed hepatocellular carcinoma (HCC)) and from 258 healthy individuals was analysed for SNPs at the coding region of the NAT2 gene by means of allele-specific polymerase chain reaction. RESULTS: There are no differences in the relative frequencies of the eight identified NAT2 alleles (including the wild-type allele) nor in the distribution of predicted phenotypes (54% of slow acetylators in each group). Twelve patients with HCC (80%) were slow acetylators (P < 0.05). CONCLUSIONS: There is no relationship between the NAT2 genotype and the risk of ALD. Slow acetylator genotype may predispose to the development of HCC in severe ALD patients not infected by the hepatitis C virus.

Adult↗

PubMedDate not supplied

[Clinical pharmacogenomics for CYP2C8 and CYP2C9: general concepts and application to the use of NSAIDs].

OBJECTIVE: To study the major mutations in genes CYP2C8 and CYP2C9, their frequency in populations of diverse ethnical descent, their analysis methods, and the major drugs with affected metabolism, with a special emphasis on NSAIDs. METHOD: Repeated searches of Pubmed (January 1966-January 2006) and Scholar Google were performed. All searches were restricted to studies in humans, and papers not written in Spanish or English were excluded. RESULTS: Ten allelic variants of CYP2C8 and 24 of CYP2C have been reported. Not all of them exert a relevant effect on drug metabolism. In Caucasians 22% of CYP2C8 genes and 31% of CYP2C9 genes have mutations. In Asians fewer than 1% and nearly 3% are mutated, respectively. Major identification methods include endonuclease digestion, PCR, pyrosequencing, and microarrays. Not all NSAIDs are exclusive substrates for CYP2C8/9. The usefulness of allelic variant analysis varies with each individual drug. The risk for digestive hemorrhage associated with the CYP2C9 genotype is particularly relevant when using aceclofenac, celecoxib, diclofenac, ibuprofen, indomethacin, lornoxicam, piroxicam, or naproxen. CONCLUSIONS: Although CYP2C8/9 activity plays an essential role in the metabolism of and clinical response to many NSAIDs, the use of pharmacogenomic techniques is not equally useful for all these drugs.

Anti-Inflammatory Agents, Non-Steroidal↗