title: Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice.
abstract: Metallothionein-I/II (MT-I/II) is a small metal-binding protein with antioxidant and neuroprotective properties, which has been used experimentally as a neurotherapeutic agent in multiple conditions. Therefore it is important to determine whether exogenous MT-I/II is retained in specific organs or expelled from the body following intramuscular and intraperitoneal injection. The distribution of exogenous MT-IIA (the major human MT-I/II isoform) was examined in MT-I/II-deficient mice, by immunohistochemistry of tissue samples and western blotting of urine samples. MT-IIA was detected within epithelial cells of the kidney cortical and medullary tubules within 1 hour of either intramuscular or intraperitoneal injection. Additionally, MT-IIA was detected within the urine at 1 hour after injection, indicating rapid absorbance into the circulation and filtration through the kidney glomerulus. A portion of the intramuscularly-injected MT-IIA remained within the muscle for at least 24 hours after injection. No MT-IIA was observed within the liver or the brain after either a single injection or a series of MT-IIA injections. These results are consistent with earlier reports that exogenously administered MT-IIA does not cross the intact blood-brain barrier, although a receptor for MT-I/II (megalin) is present in the choroid plexus. We postulate that due to losses through the urine, circulating MT-IIA levels drop rapidly after injection and do not permit transport across the choroid plexus. Peptide analogues of MT-I/II with similar neuroactive properties (emtins) may be more suited for CNS delivery.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Lewis
authors.forename: Roger S
authors.initials: RS
authors.lastname: Chung
authors.forename: Adrian K
authors.initials: AK
authors.lastname: West
authors.forename: Meng Inn
authors.initials: MI
authors.lastname: Chuah
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D008668:Metallothionein