Possible recognition of peptide derivatives by hepatic cytochrome P450 3A h
as been suggested by binding and metabolism of numerous pseudopeptidic comp
ounds such as ergot derivatives and cyclosporin.
Natural linear or cyclic dipeptides containing hydrophobic amino acids prod
uced by microorganisms and present in mammals are able to interact with the
P450 active site through either iron-amine interactions (Type II) or hydro
phobic Type I interactions. P450 3A from dexamethasone-treated rats or yeas
t-expressed P450 human 3A4 are the most potent in such interactions, which
are particularly strong with peptides containing a histidyl residue.
Some cyclodipeptides are rapidly transformed by rat cytochrome P450 3A to m
ono- or dihydroxylated metabolites, with turnovers around 3 nmoles min(-1)
P450(-1). Linear peptides are poorly transformed in these conditions. This
metabolism of cyclodipeptides occurs in 8 species including man.
Such interactions and metabolism have only minor consequences in terms of P
450 3A binding and metabolism of classical P450 3A substrates. These data r
einforce the concept that, in addition to their effect on the regulation of
P450 neosynthesis. naturally occurring endogenous peptides are also substr
ates of P450 3A. The physiological activities of these peptides may be modu
lated by their metabolism. (C) 2001 Elsevier Science Inc. All rights reserv
ed.