Low molecular weight organic acids as inhibitors of kinin-forming activity of a rodent tumor acid protease and human plasma kallikrein

Abstract

Low molecular weight organic acids were studied in vitro against the kinin-forming activity of human plasma kallikrein and an acid protease isolated from the rodent Murphy Sturm lymphosarcoma. Acids studied included β-phenyl-1-lactic, phenyl pyruvic, α-ketoglutaric, hydrocinnamic, α-keto isocaproic, phenyl acetic, 3-indole acetic, 3-indole proprionic, and ϱ-hydroxy phenyl pyruvic. The acids, studied in concentrations ranging from 1×10 −1M to 15×10 −4M were incubated for 60 minutes at 37° with human plasma kallikrein plus human kininogen substrate (in 0.4M tris buffer, pH 7.8) and with the tumor acid protease plus tumor kininogen (in 1.0M acetic acid, pH 4.0). Kinin formed was measured at pH 7.8 by bioassay on the perfused isolated rat uterus. Based on estimates of inhibitory dose 50 (ID 50), phenyl lactic, phenyl pyruvic, p-hydroxy phenyl pyruvic and α-keto isocaproic acids were most effective at concentrations 7.5×10 −3M against the tumor acid protease. Acids most effective against human plasma kallikrein in concentrations ranging from 5.0×10 −3M to 18.5×10 −3M included 3-indole proprionic, p-hydroxy phenyl pyruvic and phenyl pyruvic.