Inhibition of erythrocyte phosphoribosyltransferases (APRT and HPRT) by Pb2+ : A potential mechanism of lead toxicity

• Published in: Toxicology (Amsterdam) Vol. 259; no. 1; pp. 77 - 83
• Main Authors: Baranowska-Bosiacka, I, Dziedziejko, V, Safranow, K, Gutowska, I, Marchlewicz, M, Dołęgowska, B, Rać, M.E, Wiszniewska, B, Chlubek, D
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 02-05-2009
• Subjects: Adenine Phosphoribosyltransferase - antagonists & inhibitors; Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Emergency; Erythrocytes - drug effects; Erythrocytes - enzymology; Female; Hemolysis - drug effects; Humans; Hypoxanthine Phosphoribosyltransferase - antagonists & inhibitors; Male; Medical sciences; Metals and various inorganic compounds; Organometallic Compounds - administration & dosage; Organometallic Compounds - blood; Organometallic Compounds - toxicity; Rats; Rats, Wistar; Time Factors; Toxicology; Erythrocyte; Hemolysis; Lead (Pb 2+); Phosphoribosyltransferases; HPRT; APRT; Enzyme; Toxicity; Transferases; Glycosyltransferases; Red blood cell; Hypoxanthine phosphoribosyltransferase; Heavy metal; Blood cell; Lead II; Inhibitor; Lead (Pb2+); Inhibition; Mechanism of action; Pentosyltransferases
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2009.02.005

Abstract Many reports show that red blood cells of people exposed to lead have a decreased ATP concentration, decreased adenylate energy charge value and many metabolic and morphological abnormalities. Since the synthesis of nucleotides in erythrocytes occurs only through salvage pathways, we hypothesized that a decrease in nucleotide concentrations may be caused by lead-induced inhibition of erythrocyte phosphoribosyltransferases: adenine APRT (EC 2.4.2.7) and hypoxanthine-guanine HPRT (EC 2.4.2.8). These enzymes enable the reutilization of purine bases (adenine, guanine, hypoxanthine) converting them to mononucleotides (AMP, GMP, IMP), substrates for the synthesis of high-energy nucleotides. To confirm the hypothesis two experiments were performed: (i) in vitro , using a lysate of human erythrocytes incubated (5, 10, 30 min) with lead ions (100 μM, 10 μM, 1 μM, 500 nM, 100 nM lead acetate) and 100 μM sodium acetate for the control, (ii) in vivo , using a lysate of rat erythrocytes taken from rats chronically exposed to lead (0.1% lead acetate in drinking water for 9 months, resulting in whole blood lead concentration 7 μg/dL). The activities of APRT and HPRT were determined using HPLC method, which allowed concurrent determination of the activity of both enzymes in erythrocyte lysates. We have shown that, lead ions: (i) moderately inhibit both phosphoribosyltransferases in erythrocytes, this influence being detectable even at very low concentrations (ii) participate in hemolysis, the intensity of which negatively correlates with the activity of phosphoribosyltransferases. Our results indicate the necessity of further research on the role of lead-induced APRT and HPRT inhibition as one of the mechanisms of lead toxicity.