Important role of CYP2J2 in protein kinase inhibitor degradation: a possible role in intratumor drug disposition and resistance

• Published in: PloS one Vol. 9; no. 5; p. e95532
• Main Authors: Narjoz, Céline, Favre, Amélie, McMullen, Justin, Kiehl, Philippe, Montemurro, Michael, Figg, William D, Beaune, Philippe, de Waziers, Isabelle, Rochat, Bertrand
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.05.2014; Public Library of Science (PLoS)
• Subjects: Antibiotics; Benzamides - metabolism; Biology and Life Sciences; Biopsy; Cancer therapies; Carcinoma, Hepatocellular - genetics; Cell Line, Tumor; Chromatography; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1B1 - genetics; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Cytochromes; Dasatinib; Degradation; Drug dosages; Enzyme inhibitors; Enzyme kinetics; Gene amplification; Gene expression; Hep G2 Cells; Humans; Imatinib; Imatinib Mesylate; Indoles - metabolism; Inhibition; Kidney cancer; Kinases; Liver cancer; Liver Neoplasms - genetics; Mass spectrometry; Medicine and Health Sciences; Metabolism; Metabolites; Niacinamide - analogs & derivatives; Niacinamide - metabolism; Phenylurea Compounds - metabolism; Physical Sciences; Piperazines - metabolism; Protein Kinase Inhibitors - metabolism; Protein kinases; Protein-tyrosine kinase; Pyrimidines - metabolism; Pyrroles - metabolism; Renal cell carcinoma; Reverse Transcriptase Polymerase Chain Reaction; RNA; Scientific imaging; Sorafenib; Sunitinib; Thiazoles - metabolism; Tissues; Tumors; Tyrosine; Yang, Cindy; β Lactamase; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095532

We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined. Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation. CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.