Premium
Bimodal targeting of human cytochrome P450 2D6 to mitochondria and microsomes: A pharmacogenomic approach for identifying genetic variants defective in mitochondrial targeting
Author(s) -
Cook Michelle,
Anandatheerthavarada Hindupur,
Prabu Subbuswamy K,
Guengerich Peter Frederick,
Avadhani Narayan G
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a264-c
Subject(s) - pharmacogenomics , mitochondrion , microsome , cyp2d6 , cytochrome p450 , biology , computational biology , gene , pharmacology , genetics , biochemistry , genotype , enzyme , in vitro
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of approximately 25% of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells; however recent studies in our laboratory have identified this enzyme in the mitochondria of human liver samples, and demonstrated extensive inter‐individual variability in the mitochondrial levels. Our results show that CYP2D6 contains an N‐terminal chimeric signal that mediates its bimodal targeting to the ER and mitochondria. The mitochondrial targeting signal and protein kinase A mediated phosphorylation are both required for mitochondrial import in isolated mitochondria as well as in intact COS cells. Metabolic studies show that the mitochondrial enzyme is active in drug metabolism and that the level of enzymatic activity varies significantly between individuals. Screening of the liver samples by RT‐PCR has also enabled us to identify several variant forms with mutations involving the ER targeting signal, the proline rich domain, as well as the PKA‐specific phosphorylation site. These mutations affect the efficiency of mitochondrial targeting thus providing a valuable system to study the role of mitochondrial CYP2D6 in modulating both pharmacological efficacies and adverse toxic effects. (Supported by NIH grant GM34883 and MSTP grant 5T32GM007170).