Carcinogenicity assessment of the pan-caspase inhibitor, emricasan, in Tg.rasH2 mice.

Emricasan, formerly IDN-6556, is a small molecule currently being evaluated in clinical trials to reduce hepatic injury and liver fibrosis. Since emricasan is an irreversible pan-caspase inhibitor that potently inhibits caspase-mediated apoptosis and inflammation, its carcinogenic potential was evaluated in a humanized mouse model. Tg.rasH2 mice received LabDiet formulated with 0, 10, 25, and 75mg/kg/day of emricasan, for 26weeks. At terminal sacrifice, blood was collected for clinical pathology analysis and tissues were collected, processed, and evaluated microscopically. There were no treatment related deaths or overt signs of toxicity for the duration of the study. There was no evidence of a carcinogenic effect in the peripheral blood leukocyte counts. Liver microgranulomas, which are background lesions, were slightly increased, especially in males. Increases in the incidence of the activated germinal centers were seen in the spleens and mesenteric lymph nodes of males and females, and in the mandibular lymph nodes of male mice. Atrophy of ovaries and testicular degeneration were also seen in emricasan treated animals. Although several non-neoplastic lesions were observed, there was no evidence of emricasan-related tumor formation in any tissue. In addition, the non-neoplastic lesions were not considered pre-neoplastic. Thus, emricasan is not considered carcinogenic.

Effects of renal diseases on the regulation and expression of renal and hepatic drug-metabolizing enzymes: a review.

1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidneys. Generally, the kidneys contain most, if not all, of the DMEs found in the liver. Surprisingly, some of these DMEs show higher activity in the kidneys than in the liver. 2. Most of the renal DMEs are localized in the cortex of the kidneys, especially in the proximal tubules. DMEs are also found in the distal tubules and collecting ducts. 3. Renal diseases such as acute and chronic renal failure and renal cell carcinoma alter the regulation of both hepatic and extrahepatic phase I and II DMEs. Changes in the expression of these DMEs seem to be tissue and species specific. 4. Generally, there is significant down-regulation of most of the phase I and a few of phase II DMEs at the protein, mRNA and activity levels. Unfortunately, the mechanisms leading to the alteration in DMEs in renal diseases remain unclear, although many theories have been made. 5. The presence of some circulating factors such as cytokines, nitric oxide, parathyroid hormones and increased intracellular calcium play a role in the regulation of DMEs in renal diseases.