Transport of histone through the blood-brain barrier.
The present studies were designed to determine if the endogenous cationic protein, e.g., histone, is capable of penetrating the blood-brain barrier (BBB) in vivo. Calf thymus histone was iodinated with [125I]iodine and was found to be taken up rapidly by isolated bovine brain capillaries used as an in vitro model system of the BBB via a time- and temperature-dependent mechanism. The binding was saturable and a Scatchard plot of the binding data was linear, yielding a KD = 15.2 +/- 2.8 microM and a maximal binding = 7.7 +/- 1.0 nmol/mg of protein. Other polycations such as protamine or polylysine markedly inhibited uptake of [125I] histone, but cationized albumin demonstrated minimal inhibition and cationized immunoglobulin caused no inhibition of bovine brain capillary uptake of [125I]histone. The in vivo brain VD of [125I] histone reached 159 +/- 70 microliters/g by 10 min of carotid arterial perfusion as compared to the 10-min VD for [3H]albumin, 17 +/- 7 microliter/g. Most of this uptake represented sequestration by the vasculature, but approximately 8% of the total histone taken up by brain was found to be transported unmetabolized (based on trichloroacetic acid precipitability of brain supernatant [( 125I]) into brain interstitium. These studies demonstrate that histone is transported through the BBB in vivo via absorptive-mediated transport. Thus, histone is an endogenous protein that is capable of transport through the BBB and may be a potential vector for pharmaceutical delivery through the BBB.
Pardridge
W M
WM
Department of Medicine, University of California, Los Angeles School of Medicine.
Triguero
D
D
Buciak
J
J
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002417:Cattle; D004337:Drug Carriers; D006657:Histones / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000493:pharmacokinetics
D004337:Drug Carriers; D006657:Histones; D012709:Serum Albumin