Formation of cobalt protoporphyrin in the liver of rats. A mechanism for the inhibition of liver haem biosynthesis by inorganic cobalt

Abstract

Treatment of rats with small doses of CoCl2 decreases liver 5-aminolevulinate synthase (EC 2.3.1.37) activity and impairs incorporation of 5-amino[14C]levulinate into liver heme. Salts of other metals (Cd, Ni, Mn and Zn) are all relatively inactive. The dose-response curves obtained for both these effects closely mirror the accumulation in the liver of a compound that is labeled by 5-amino[14C]levulinate and is unextractable by acetone/HCl. Incorporation of 5-amino[14C]levulinate into unextractable compound is also obtained in vitro by incubating liver homogenates with label in the presence of Co; isotope-dilution experiments show that the radioactivity passes through pools of porphobilinogen and protoporphyrin, but not of heme. The unextractable compound is not covalently bound to protein and posesses the same extraction and spectral properties as authentic cobalt protoporphyrin. Co protoporphyrin is readily formed in vitro and in vivo; its formation accounts for the impaired incorporation of 5-aminolevulinate into heme and may also be responsible for the action of Co on 5-aminolevulinate synthase.