Cytochrome P450 3A degradation in isolated rat hepatocytes: 26S proteasome inhibitors as probes.

Abstract

Mechanism-based inactivation of liver microsomal cytochromes P450 3A (CYP 3A, P450s 3A) in vivo and/or in vitro, via heme modification of the protein, results in accelerated proteolytic degradation of the enzyme that is preceded by the ubiquitination of the protein, thereby implicating the ubiquitin-ATP-dependent 26S proteasomal system. In this study, this involvement is confirmed with the use of the proteasomal inhibitors aclarubicin and MG-132 as probes, in isolated rat hepatocytes treated with the P450 3A mechanism-based inactivator, 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1, 4-dihydropyridine (DDEP). In addition, the findings reveal that during the course of this proteolysis, the endoplasmic reticulum (ER)-anchored DDEP-inactivated P450 3A is translocated from the ER to the cytosol in a brefeldin A-insensitive manner.

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@article{Wang1999CytochromeP3, title={Cytochrome P450 3A degradation in isolated rat hepatocytes: 26S proteasome inhibitors as probes.}, author={H Wang and M E Figueiredo Pereira and Maria Almira Correia}, journal={Archives of biochemistry and biophysics}, year={1999}, volume={365 1}, pages={45-53} }