Dl-α-Hydrazinoimidazolylpropionic acid: An irreversible inhibitor of hepatic histidine ammonia-lyase in vivo

Abstract

dl-α-Hydrazinoimidazolylpropionic acid ( dl-HIPA), a potent competitive inhibitor of rat liver histidine ammonia-lyase, was found to produce a partial (more than 70%) inactivation of this enzyme in vivo when administered intraperitoneally to rats. This inactivation was irreversible, as demonstrated by the failure of prolonged dialysis to restore the histidine ammonia-lyase activity of liver extracts from dl-HIPA treated rats and by the extended duration of the depression of enzyme activity following injection of this compound. The inactivation phenomenon was dose-dependent and specific for dlHIPA; administration of other hydrazine compounds to rats was without effect on hepatic histidine ammonia-lyase activity. Although dl-HIPA produced only slight inactivation of partially purified rat liver histidine ammonia-lyase in vitro, this process was greatly enhanced by the combined presence in the incubation medium of liver microsomes, NADPH, and O 2. Rats pretreated with phenobarbital were found to be significantly more sensitive to histidine ammonia-lyase inactivation in vivo following dl-HIPA administration than were saline-injected controls. These findings suggest dl-HIPA to inactivate rat liver histidine ammonia-lyase in vivo by a specific, indirect mechanism, possibly involving the prior interaction of this compound with a microsomal mixed-function oxidase.