Transcriptional repression of hepatic cytochrome P450 3A4 gene in the presence of cancer.
OBJECTIVE
Many chemotherapeutic drugs have an inherent lack of safety due to interindividual variability of hepatic cytochrome P450 (CYP) 3A4 drug metabolism. This reduction in CYP3A4 in cancer patients is possibly mediated by cytokines associated with tumor-derived inflammation. We sought to examine this link by using an explant sarcoma in a novel transgenic mouse model of human CYP3A4 regulation.


METHODS
Engelbreth-Holm-Swarm sarcoma cells were injected into the hindlimb of transgenic CYP3A4/lacZ mice. Hepatic expression of the human CYP3A4 transgene was analyzed by direct measurement of the reporter gene product, beta-galactosidase enzyme activity. Hepatic expression of murine Cyp3a was analyzed at the mRNA, protein, and function levels. The acute phase response was assessed by examining cytokines [interleukin-6 (IL-6) and tumor necrosis factor] in serum, liver, or tumor as well as hepatic expression of serum amyloid protein P.


RESULTS
Engelbreth-Holm-Swarm sarcoma elicited an acute phase response that coincided with down-regulation of the human CYP3A4 transgene in the liver as well as the mouse orthologue Cyp3a11. The reduction of murine hepatic Cyp3a gene expression in tumor-bearing mice resulted in decreased Cyp3a protein expression and consequently a significant reduction in Cyp3a-mediated metabolism of midazolam. Circulating IL-6 was elevated and IL-6 protein was only detected in tumor tissue but not in hepatic tissue.


CONCLUSIONS
The current study provides a mechanistic link between cancer-associated inflammation and impaired drug metabolism in vivo. Targeted therapy to reduce inflammation may provide improved clinical benefit for chemotherapy drugs metabolized by hepatic CYP3A4 by improving their pharmacokinetic profile.
Charles
Kellie A
KA
Department of Pharmacology, University of Sydney, Sydney, New South Wales, Australia.
Rivory
Laurent P
LP
Brown
Sandie L
SL
Liddle
Christopher
C
Clarke
Stephen J
SJ
Robertson
Graham R
GR
D000759:Adjuvants, Anesthesia / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008874:Midazolam / Q000378:metabolism / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D000759:Adjuvants, Anesthesia; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D001616:beta-Galactosidase; D008874:Midazolam