Substrate-, hormone-, and cAMP-regulated cytochrome P450 degradation.
The hepatic cytochrome P450 system, with numerous different P450 enzymes, is characterized by its inducibility by a variety of endogenous and exogenous compounds. Specific forms of P450, exhibiting distinct but partially overlapping substrate specificities, are increased in response to a given chemical. Consequently, the rate of elimination of the inducing compound is often enhanced and the system is in this respect adaptive to changes in the environment. Transcriptional activation mechanisms for the endo- or xenobiotically controlled P450 synthesis are well documented. Here we describe a mechanism for posttranslational ligand-dependent stabilization of ethanol-inducible P450IIE1 in hepatocyte cultures. Glucagon or 8-bromoadenosine 3',5'-cyclic monophosphate causes an enhanced rate of P450IIE1 degradation in the hepatocytes as well as phosphorylation on Ser-129, a reaction which denatures the protein under in vitro conditions. Substrates for the enzyme, such as ethanol and imidazole, protect the enzyme from phosphorylation and degradation in hepatocytes but do not influence phosphorylation or degradation of phenobarbital-inducible P450IIB1. Our proposed mechanism, which remains to be shown under in vivo conditions, describes the P450 molecules as receptors for the compounds in question and might provide a way by which endo- and xenobiotics regulate their own rate of metabolism.
Eliasson
E
E
Department of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden.
Johansson
I
I
Ingelman-Sundberg
M
M
D000433:1-Propanol / Q000494:pharmacology*; D000096:Acetone / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005934:Glucagon / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D000096:Acetone; D000431:Ethanol; D005934:Glucagon; D003577:Cytochrome P-450 Enzyme System; D000433:1-Propanol; D010634:Phenobarbital