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

Serum and liver iron concentration in dogs with experimentally induced hepatopathy

Background and Aim: Iron (Fe) status is altered in human and experimental animal hepatopathies. In dogs limited data are available. The aim of this study was to investigate serum iron (SI), total iron binding capacity (TIBC), percentage transferrin saturation (SAT) and Fe status in the liver of dogs with experimentally induced hepatopathy. Methods: Fourteen 1-year-old dogs were divided into two equal groups. In order for hepatopathy to be induced, 0.25 mL/kg body weight of carbon tetrachloride (CCl4) solution was administered once daily, orally, for a 10-week period in group B dogs, while group A dogs were used as controls. SI, TIBC and SAT values were measured 3 times before the beginning (baseline value) and 10 times at weekly intervals during the experiment. Liver samples, obtained before the administration of CCl4 and at the end of the experimental period (10 weeks), were subjected to Fe determination, as well as to histopathological and histochemical analysis. Results: At the end of the experiment SI, TIBC and liver iron concentration, as well as liver total iron score were significantly increased in group B dogs. Distribution of granular hemosiderin iron in hepatocytes, Kupffer cells, and portal triads was noticed. Positive correlations were found between SI and liver Fe concentration, as well as histochemically determined Fe. Moreover, positive correlations were evident between liver fibrosis and serum, as well as liver Fe values. Conclusions: Experimentally induced chronic hepatopathy in dogs causes Fe status disturbances. Increased serum and liver iron concentration produces liver histopathological deterioration and it may be worth attention during laboratory evaluation in canine hepatopathy. (C) 2005 Blackwell Publishing Asia Pty Ltd