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J. Biochem, 1982, Vol. 91, No. 4 1373-1380
© 1982 Japanese Biochemical Society

research-article

Inhibitions of Cathepsin B and Cathepsin L by E-64 In Vivo. II. Incorporation of [3H]E-64 into Rat Liver Lysosomes In Vivo1

Seiichi HASHIDA, Eiki KOMINAMI and Nobuhiko KATUNUMA

Department of Enzyme Chemistry, Institute for Enzyme Research, School of Medicine, Tokushima University Tokushima, Tokushima 770

E-64 is a specific thiol proteinase inhibitor which inhibits lysosomal cathepsins B and L in vitro and in vivo [Hashida, S., Towatari, T., Kominami, E., & Katunuma, N. (1980) J. Biochem. 88, 1805–1811]. This work showed that E-64 administered in vivo penetrates into lysosomes of the liver, possibly by permeation rather than by endocytosis. When [3H]E-64 was injected into rats i.p., high radioactivity was observed in the serum after a short time and it decreased rapidly. Incorporation of [3H]E-64 into the cytosol fraction of liver also began to decrease 1 h after the injection. Radioactivity in the mitochondrial-lysosomal fraction increased to a maximum after 6 h and then gradually decreased until 72 h. Dose-dependent incorporation of [3H]E-64 into the serum and liver cytosol was observed at all doses tested, but that into the lysosomal fraction increased linearly with doses of only up to 0.5 mg/100 body weight of E-64. E-64 in the serum and liver cytosol was mostly present in the free form, whereas that in the lysosomal fraction was mostly protein-bound. The time course and dose-response of lysosomal cathepsin B activity to E-64 were closely related to the radioactivity in the protein-bound fraction of the lysosomes.

These results suggest that E-64 was transported to the liver cytosol in the free form in the blood and permeated into the lysosomes, where it bound to, and inactivated, E-64 sensitive proteinases.

1This work was supported by a Grant for Research on Development of the New Drug E-64 from the Ministry of Health and Welfare of Japan (1980).


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