Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies.
There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
R
R
Sharma
M
M
Kacevska
R
R
London
S J
SJ
Clarke
C
C
Liddle
G
G
Robertson
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005260:Female; D007249:Inflammation; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000008:administration & dosage*; D017286:Polysomnography; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000209:Acute-Phase Proteins; D014151:Anti-Anxiety Agents; D016207:Cytokines; D015850:Interleukin-6; D008565:Membrane Proteins; D012333:RNA, Messenger; C095122:multidrug resistance protein 3; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam