Impact of inflammation on drug clearance pathways in cancer: Repression of hepatic CYP3A and drug transporter genes by tumor-derived cytokines

B26

A major challenge in pharmacogenomics is the narrow therapeutic index of anti-cancer treatments, as toxicity due to variable drug clearance is a common cause of treatment failure. CYP3A4 is the major pathway of human drug metabolism, responsible for clearance of over half of all anti-cancer agents. While many studies have sought to establish links between CYP3A4 polymorphisms and altered pharmacokinetics of anti-cancer agents, genetic differences do not appear to account for variable CYP3A-mediated drug metabolism in cancer. Recently, we observed that reduced CYP3A4 activity in cancer patients was correlated to the degree of systemic inflammation, resulting in enhanced toxicity of anti-cancer drugs (1). To investigate hepatic expression of the human CYP3A4 gene in the presence of cancer, we used a transgenic mouse model (2) of the CYP3A4 regulatory region attached to lacZ. The EHS sarcoma was injected into the hind limb of transgenic CYP3A4/lacZ mice. Markers of inflammation included cytokine levels and hepatic expression of Serum Amyloid protein P (SAP), the major mouse acute phase protein. Assessment of CYP3A function by the midazolam sleep test showed that midazolam-induced anaesthesia was increased in tumour-bearing mice. Hepatic CYP3A4 and mouse Cyp3a11 expression was decreased in tumour-bearing animals, while SAP expression was increased 8 fold. The expression of other CYPs and drug transporters including Mrp2, Mrp3, Oatp2, Oatpc, MDR2 and Bcrp was also down-regulated in the liver. Evidence for the involvement of IL-6 included raised serum concentrations, increased phospho-STAT3 protein, activated MAP kinases and SOCS3 mRNA levels in the liver. We have also observed reduced CYP3A and drug transporters associated with inflammation in mice with breast, melanoma and colon explant tumours showing that repression of drug clearance pathways is a feature of diverse cancers. As the nuclear receptor PXR regulates drug clearance pathways including CYP3A4, we determined the activity of PXR in tumour bearing mice. PXR response was markedly reduced in the presence of the EHS sarcoma indicating interactions between tumour derived inflammation and the pivotal regulator of drug clearance. CONCLUSIONS This study has shown for the first time that cancer-associated inflammation transcriptionally represses drug clearance pathways. The transgenic mouse model of human CYP3A4 regulation, coupled with explant tumour models, permits pre-clinical testing of anti-inflammatory interventions aimed at making cancer treatment safer and more effective. Reduced levels of hepatic drug transporters, as opposed to enhanced expression within cancer cells, has significant implications for the management of multi-drug resistance in tumours. Consideration of the impact of inflammation associated with tumours on the pharmacokinetics of anti-cancer drugs may make a significant contribution to individualised treatment.1) Slaviero K et al 2003 Lancet Oncology, 4:224-322) Robertson GR et al 2003 Molecular Pharmacology, 64:42-50