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Molecular Determinants in the Plasma Clearance and Tissue Distribution of Ribonucleases of the Ribonuclease A Superfamily

Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892 [V. M. V., Y-N. W., R. J. Y.]; Alfacell Corporation, Bloomfield, New Jersey 07003 [S. M. M.]; and Biomedical Engineering and Instrumentation Program, National Center for Research Resources, NIH, Bethesda, Maryland 20892 [C. S.]

The similarities and differences among members of the RNase A superfamily provide an ideal opportunity to examine the molecular basis for differences in their pharmacokinetics and biodistribution. Plasma clearances in BALB/c mice are similar among the five RNases studied: human pancreatic RNase, angiogenin, eosinophil-derived neurotoxin, onconase, and bovine seminal RNase. The average clearance is 0.13 ml/min or 60% of the glomerular filtration rate (measured by [¹⁴C]inulin clearance during continuous infusion from an i.p. implanted osmotic pump). Angiogenin has a higher volume of distribution and plasma-to-muscle transport rate than the other RNases, suggestive of binding to endothelial cells. Organ distribution differs dramatically among these RNases. The RNase most toxic to tumor cells, onconase, exhibits the longest retention in the kidneys: at 180 min, 50% of the injected dose is found in the kidneys, whereas only 1% or less of the other RNases is retained in the kidneys. Slower elimination of onconase from the kidneys may be due to a higher degree of binding in the kidney or a resistance to proteolytic degradation. To elucidate the molecular determinants involved in tissue uptake, we examined the biodistribution of recombinant onconase and two onconase-pancreatic RNase chimeric proteins. The tissue retention property of onconase appears to be located in at least two regions, one of which is in the NH₂-terminal 9-amino acid -helix. The NH₂-terminal pyroglutamate of onconase, a residue essential for ribonucleolytic activity and cytotoxicity, does not play a role in kidney retention.

¹ Present address: Department of Anaesthesia, Brigham and Women's Hospital, Harvard, 75 Francis Street, Boston, MA 02115.

² To whom requests for reprints should be addressed, at NIH, Building 13, Room 3N17, Bethesda, MD 20892-5766. Phone: (301) 496-5771; Fax: (301) 496-6608.

Received 4/10/96. Accepted 7/16/96.

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