Inhibition of l-asparagine synthetase by mineral cations

Abstract

The inhibition of l-asparagine synthetase from Leukemia 5178Y AR and mouse pancreas by mineral cations was examined. Of the 24 agents tested in vitro, 5 (cadmium chloride, cupric chloride, mercuric chloride, mercurous chloride, and zinc chloride) inhibited the utilization of l-glutamine and NH 4Cl by the enzymes by nearly 90% at a concentration of 1 m m; 4 other compounds (calcium chloride, cobaltous chloride, cuprous chloride, and manganous chloride) inhibited the utilization of l-glutamine and NH 4Cl by the synthetases by more than 50%. The in vitro inhibition of l-asparagine synthetase by zinc chloride, a prototypical example of this class of compounds, was partially reversed (approximately 55%) by dialysis. Moreover, the compound inhibited the l-glutaminase activity of partially purified l-asparagine synthetase from mouse pancreas by 70% at a concentration of 3 m m. In vivo, zinc chloride inhibited preferentially the pancreatic enzyme with no significant inhibition of the enzyme in tumor when administered ip as a single injection (100 mg/kg) or when given daily for 5 days (20 mg/kg) to BDF 1 mice bearing subcutaneous implants of Leukemia 5178Y AR ; the concentration of l-asparagine in tumor or pancreas was not unduly affected by either treatment regimen. That the preferential effect on enzyme activity may be more apparent than real is suggested by the observed pancreatitis produced by this agent. It can be concluded that while zinc chloride may not be a suitable agent for overcoming the state of resistance to l-asparaginase therapy in acute lymphocytic leukemia, its toxic effects on the exocrine pancreas are of importance and warrant further investigation.