Reversible dimerization of 20 kilodalton human growth hormone (hGH).
A noncovalent dimer of the 22 kilodalton human growth hormone (22 K-hGH) is known to have diminished somatogenic activity compared with monomeric 22 K-hGH. In the present study, we examined the biological activity and physicochemical behaviour of a noncovalent dimer of the 20 kilodalton human growth hormone (20 K-hGH), an isoform of 22 K-hGH. Analysis of the equilibrium between monomeric and associated forms revealed that the associated 20 K-hGH was present in the dimeric form in aqueous solution. The kinetics of dimerization in rat plasma followed the theory of dissociation-association equilibrium, and more than 99% of 20 K-hGH molecules existed as a monomer in the equilibrium state at the physiological hGH concentration. Analysis of the pharmacokinetics showed that the ratio of the administrated dimer in rat circulation decreased from 43% to less than 4% in 2 h. A preparation of noncovalent dimeric 20 K-hGH had essentially the same degree of biological potency as that of a monomer in both in vitro and in vivo bioassays. In conclusion, dimerization of 20 K-hGH is reversible both in vitro and in vivo and a noncovalent dimer can function as a pharmaceutically active component of a 20 K-hGH preparation, in contrast to a 22 K-hGH preparation.
Nagatomi
Y
Y
Life Science Laboratories, Mitsui Chemicals Inc, Mobara, Chiba, Japan. yugi.nagatomi@mitsui-chem.co.jp
Ikeda
M
M
Uchida
H
H
Wada
M
M
Kobayashi
H
H
Hashimoto
Y
Y
Mabuchi
K
K
Hayakawa
M
M
Kusuhara
N
N
Honjo
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019281:Dimerization; D006128:Growth / Q000187:drug effects; D019382:Human Growth Hormone / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008970:Molecular Weight; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
D019382:Human Growth Hormone