Hepatic CYPs 3A and CYP2E1 are monotopic, endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) responsible for the biotransformation of various xenobiotics including therapeutic drugs. Alterations of P450 protein turnover can influence drug metabolism, drug-drug interactions and drug bioavailability and thus are clinically relevant. CYP3A turnover occurs via an ER-associated degradation (ERAD) process, while that of CYP2E1 incurs both ERAD and autophagic lysosomal degradation. We have documented that such P450 ERAD involves the sequential and cooperative function of UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes that covalently attach one or more P450 Lys-residues with polyubiquitin chains and mark these proteins for ER-extraction by the p97 AAA-ATPase and subsequent degradation by the 26S proteasome. RNAi knockdown of each E3-ligase in cultured hepatocytes stabilizes not only the inactive ubiquitinated P450s but also surprisingly their functionally active species, thereby regulating the hepatic P450 content that is functionally available. Protein phosphorylation by protein kinase (PK) A and PKC significantly enhances UBC7/gp78- and UbcH5a/CHIP-mediated P450 ubiquitination. We have identified multiple phosphorylated Ser/Thr residues and ubiquitinated Lys-residues in both P450s through proteomic analyses. Inspection of the P450 structures reveals that these ubiquitinated P450 Lys-residues reside within negatively charged, spatially associated surface clusters of Asp/Glu and phosphorylatable Ser/Thr residues. Ser/Thr-phosphorylation within these clusters would further enhance their negatively charged character by filling in the missing gaps. We propose that such clusters function as "conformational phosphodegrons" to engage UBC7/gp78 and/or UbcH5a/CHIP and thus control the timing of their molecular recognition of P450s as substrates. Collectively, our findings establish a firm link between posttranslational multisite protein phosphorylation and P450 ubiquitination/ERAD. Supported by NIH Grants GM44037, DK26506 and DK26743.