Altered Arylamine N-acetyltransferase 1 and miR-1290 Levels in Childhood Acute Lymphoblastic Leukemia: A Pilot Study.

BACKGROUND/AIM: Arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) are drug-metabolizing enzymes that play a key role in the development of acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: This study evaluated NAT1 and NAT2 mRNA and protein expression and their enzymatic activity in peripheral blood mononuclear cells (PBMC) from patients with ALL (n=20) and healthy children (n=19) and explored the mechanisms that regulate these enzymes in ALL such as microRNAs (miR-1290, miR-26b) and SNPs. RESULTS: PBMC from patients with ALL showed a decrease in NAT1 mRNA and protein expression. In addition, NAT1 enzymatic activity was decreased in patients with ALL. There was no influence of SNP 559 C>T or 560 G>A on low NAT1 activity. The lower expression of NAT1 might be related to the loss of acetylated histone H3K14 in the NAT1 gene promoter in patients with ALL and the higher relative expression of miR-1290 in the plasma of patients with relapsed ALL compared with healthy controls. There were significantly fewer CD3+/NAT1+ double-positive cells in patients who relapsed compared with control subjects. Based on a t-distributed stochastic neighbor embedding algorithm, CD19+ cells that reappeared in patients with relapse showed low NAT1 expression. In contrast, for NAT2, there were no significant results. CONCLUSION: The expression and function of NAT1 and miR-1290 levels could be involved in modulating immune cells altered in ALL.

The role of arylamine N-acetyltransferases in chronic degenerative diseases: Their possible function in the immune system.

Since their discovery, arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2, respectively) have been associated with the metabolism of xenobiotics. NAT2 is the main factor in the therapeutic success of tuberculosis treatment due to its role in the biotransformation of isoniazid. However, researchers have started to investigate the possible participation of NAT1 and NAT2 (NATs) in carcinogenesis, although the mechanisms have not been elucidated fully. NATs enzymatic activity is essential in some types of cancer, such as breast cancer and acute lymphoblastic leukemia. Whether NAT1 and/or NAT2 participate in insulin resistance level in diabetes mellitus or in the immune system remains to be explored. Therefore, it is clear that its role in cell physiology has more implications than just metabolizing compounds.

Quantification of pyrazinamide, isoniazid, acetyl-isoniazid, and rifampicin by a high-performance liquid chromatography method in human plasma from patients with tuberculosis.

The aim of this study was to establish and validate an alternative high-performance liquid chromatography method for simultaneous quantification of pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin in plasma of patients under treatment for tuberculosis. The performed method was lineal (r2  > 0.99) in the range of 2.00-50.00 µg/mL for pyrazinamide, 0.50-20.00 µg/mL for both acetyl-isoniazid and isoniazid, and 1.20-25.00 µg/mL for rifampicin. Precision and trueness were demonstrated with coefficient of variation < 15% and deviations < 15%, respectively, for quality controls samples. The lower limits of quantification were 2.00, 0.50, 0.50, and 1.20 µg/mL for pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin, respectively. The method was applied for the analysis of plasma from patients with tuberculosis. This method allowed ensuring reliable quantification of the target compounds and their pharmacokinetics parameters. In general, the mean values of maximum concentration of each antituberculosis drug were located within their respective reference therapeutic ranges. However, patients with sub-therapeutic plasma concentrations of isoniazid and rifampicin were detected. This is the first analytical technique that simultaneously quantifies isoniazid, acetyl-isoniazid, rifampicin, and pyrazinamide concentrations from plasma samples by high-performance liquid chromatography with ultraviolet/visible. The proposed method could be applied for therapeutic drug monitoring and pharmacokinetics studies of the four compounds throughout the treatment of tuberculosis patients.

[Asociación del estado hormonal con el riesgo cardiovascular evaluado por Globorisk en mujeres mexicanas].

INTRODUCTION: Cardiovascular disease is the main cause of mortality worldwide. In women, its incidence increases at the sixth decade of life, coinciding with postmenopause. Whether this effect is due to menopause-related hormonal changes is not known. OBJECTIVE: To evaluate the differences in cardiovascular risk in pre- and postmenopausal women by means of the Globorisk risk scale, the triglyceride/high-density lipoproteins cholesterol (Tg/HDL-C) ratio and metabolic syndrome (MS) criteria. METHOD: Cross-sectional study that included 408 women from 40 to 60 years of age; anthropometric measurements and biochemical determinations were performed. The participants were classified as premenopausal and postmenopausal. Cardiovascular risk was assessed using the MS criteria, the Globorisk risk calculator and the Tg/HDL-C ratio. RESULTS: Postmenopausal women showed a significant increase in waist circumference, total cholesterol and triglycerides in comparison with premenopausal women. Significant associations were found between hormonal state and Globorisk measured cardiovascular risk (OR = 2.50; 95 % CI = 1.67-3.74) and the Tg/HDL-C ratio (OR = 1.66; 95 % CI = 1.09-2.52). CONCLUSION: Cardiovascular risk factors have a higher prevalence in postmenopause. The Globorisk scale and Tg/HDL-C ratio identify cardiovascular risk in postmenopausal women.

INTRODUCCIÓN: La enfermedad cardiovascular es la principal causa de mortalidad en el mundo. En la mujer se incrementa en la sexta década de la vida, coincidiendo con la posmenopausia. Se desconoce si este efecto se debe a cambios hormonales relacionados con la menopausia. OBJETIVO: Evaluar diferencias del riesgo cardiovascular en mujeres pre y posmenopáusicas mediante la escala de riesgo Globorisk, el índice triglicéridos/c-HDL (Tg/c-HDL) y los criterios de síndrome metabólico (SM). MÉTODOS: Estudio transversal que incluyó a 408 mujeres de 40 a 60 años; se realizaron mediciones antropométricas y bioquímicas. Las participantes se clasificaron en premenopáusicas y posmenopáusicas. El riesgo cardiovascular se evaluó utilizando los criterios de SM, calculadora de riesgo Globorisk y el índice Tg/c-HDL. RESULTADOS: Las mujeres en etapa posmenopáusica presentaron incremento significativo en la circunferencia de cintura, de colesterol total y triglicéridos, en comparación con las mujeres premenopáusicas. Se encontraron asociaciones significativas del estado hormonal con el riesgo cardiovascular evaluado por Globorisk (RM = 2.50, IC 95 % = 1.67-3.74) y con el índice Tg/c-HDL (RM = 1.66, IC 95 % = 1.09-2.52). CONCLUSIÓN: Los factores de riesgo cardiovascular tienen mayor prevalencia en la posmenopausia. La escala Globorisk y el índice Tg/c-HDL identifican el riesgo cardiovascular en la mujer posmenopáusica.

Genetic polymorphisms of arylamine N-acetyltransferases 1 and 2 and the likelihood of developing pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the main causes of death in children and is associated with both genetic susceptibility and environmental factors. Genes encoding the arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2) isoenzymes are highly polymorphic among populations. Single-nucleotide polymorphism analysis was performed by real-time polymerase chain reaction from the genomic DNA of 225 healthy subjects and 57 children with ALL diagnoses. Significant associations were found between the development of ALL and the presence of the haplotypes NAT1*3 (Odds ratio [OR], 2.1), NAT1*4 (OR, 1.92), NAT2*6B (OR, 3.30), NAT2*6J (OR, 3.25) and NAT2*7A (OR, 2.45) and the NAT1 rapid (OR, 6.69) and NAT2 slow phenotypes (OR, 2.95). Our results indicate that haplotypes that provide rapid NAT1 and slow NAT2 acetylating phenotypes may influence the development of ALL in children.