Effects of bedding substrates on microsomal enzymes in rabbit liver.

Previous studies have reported that housing rats and mice on softwood beddings induce microsomal enzymes. To date, no published studies investigate effects of softwood beddings on microsomal induction in rabbits. The purpose of this study was to determine whether microsomal enzymes, primarily cytochromes P450 3A and 2B, were induced in rabbits exposed to commonly used bedding substrates. Rabbits were placed in cages 7.6 cm above 1 sheet of 24 x 36 in. postconsumer recycled paper, approximately 16 cups (130 ounces) of pine shavings, or no substrate. Positive-control rabbits were given either rifampin (50 mg/kg) or phenobarbital (60 mg/kg) intraperitoneally once daily for 5 d. At 2, 7, and 14 d after placement in test cages, rabbits were euthanized and the livers harvested. Microsomal pellets were prepared from the livers and used in an erythromycin Ndemethylase assay (to determine CYP3A activity) and a pentoxyresorufin-O-deethylation assay (to determine CYP2B activity). Although the levels of enzyme induction varied slightly in both assays, statistical significance was not reached compared to the positive-control levels. These results indicate that neither CYP450 3A or 2B enzymes are induced by exposure of rabbits to pine shavings or paper substrate as noncontact bedding for up to 14 d.

Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury.

A major drawback to doxorubicin as a cancer-treating drug is cardiac toxicity. To understand the mechanism of doxorubicin cardiac toxicity and the potent synergic effect seen when doxorubicin is combined with anti-ErbB2 (trastuzumab), we developed an in vivo rat model that exhibits progressive dose-dependent cardiac damage and loss of cardiac function after doxorubicin treatment. The hearts of these animals respond to doxorubicin damage by increasing levels of ErbB2 and the ErbB family ligand, neuregulin 1beta, and by activating the downstream Akt signaling pathway. These increases in ErbB2 protein levels are not due to increased ErbB2 mRNA, however, suggesting post-transcriptional mechanisms for regulating this protein in the heart. Accordingly, levels of heat shock protein 90 (HSP90), a known ErbB2 protein stabilizer and chaperone, are increased by doxorubicin treatment, and coimmunoprecipitation reveals binding of HSP90 to ErbB2. Isolated cardiomyocytes are more susceptible to doxorubicin after treatment with HSP90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin, suggesting that the HSP90 is protective during doxorubicin treatment. Thus, our results provide one plausible mechanism for the susceptibility of the heart to anti-ErbB2 therapy post-doxorubicin therapy in subclinical and clinical conditions. Additionally, these results suggest that further testing is needed for HSP90 inhibitors under various conditions in the heart.