Hepatic cytochrome P450 degradation: mechanistic diversity of the cellular sanitation brigade

Drug Metab Rev. 2003 May-Aug;35(2-3):107-43. doi: 10.1081/dmr-120023683.

Abstract

Hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins that exhibit heterogenous physiological protein turnover. The molecular/cellular basis for such heterogeneity is not well understood. Although both autophagic-lysosomal and nonlysosomal pathways are available for their cellular degradation, native P450s such as CYP2B1 are preferentially degraded by the former route, whereas others such as CYPs 3A are degraded largely by the proteasomal pathway, and yet others such as CYP2E1 may be degraded by both. The molecular/structural determinants that dictate this differential proteolytic targeting of the native P450 proteins remain to be unraveled. In contrast, the bulk of the evidence indicates that inactivated and/or otherwise posttranslationally modified P450 proteins undergo adenosine triphosphate-dependent proteolytic degradation in the cytosol. Whether this process specifically involves the ubiquitin (Ub)-/26S proteasome-dependent, the Ub-independent 20S proteasome-dependent, or even a recently characterized Ub- and proteasome-independent pathway may depend on the particular P450 species targeted for degradation. Nevertheless, the collective evidence on P450 degradation attests to a remarkably versatile cellular sanitation brigade available for their disposal. Given that the P450s are integral ER proteins, this mechanistic diversity in their cellular disposal should further expand the repertoire of proteolytic processes available for ER proteins, thereby extending the currently held general notion of ER-associated degradation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Biotransformation
  • Cytochrome P-450 Enzyme System / metabolism*
  • Cytosol / enzymology*
  • Humans
  • Liver / enzymology*
  • Peptide Hydrolases / metabolism
  • Proteasome Endopeptidase Complex*

Substances

  • Cytochrome P-450 Enzyme System
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease