Cellular proteolytic systems in P450 degradation: evolutionary conservation from Saccharomyces cerevisiae to mammalian liver

Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):33-49. doi: 10.1517/17425255.3.1.33.


Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored haemoproteins with the bulk of their catalytic domains exposed to the cytosol and engaged in the metabolism of numerous xeno- and endobiotics. The native P450s exhibit widely ranging half-lifes and predominantly turn over via either autophagic-lysosomal degradation (ALD) or ubiquitin-dependent 26S proteasomal degradation (UPD). The basis for this heterogeneity and differential proteolytic targeting is unknown. On the other hand, structurally/functionally inactivated P450s are predominantly degraded via UPD in a process known as ER-associated degradation (ERAD). ALD/UPD/ERAD pathways are evolutionarily highly conserved. The availability of Saccharomyces cerevisiae mutants with specific genetic defects/deletions in various ALD/UPD/ERAD-associated proteins and corresponding isogenic wild-type strains has enabled the molecular dissection of the degradation pathways for heterologously expressed mammalian P450s, leading to the identification of specific protein participants. These findings collectively attest to a highly versatile cellular system for the physiological disposal of native, senescent and/or inactivated, structurally damaged mammalian liver P450s.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Evolution, Molecular
  • Humans
  • Liver / metabolism
  • Lysosomes / metabolism*
  • Models, Biological
  • Peptide Hydrolases / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics


  • Cytochrome P-450 Enzyme System
  • Peptide Hydrolases