COMPARATIVE METABOLISM OF LOW CONCENTRATIONS OF BUTADIENE AND ITS MONOEPOXIDE IN HUMAN AND MONKEY HEPATIC MICROSOMES

The chronic (2-yr) inhalation toxicity of 1,3-butadiene (BD), a chemical used in large quantities to make rubber and plastics, differs greatly between mice and rats. Mice develop lung tumors after exposures to concentrations as low as 6.25 ppm, whereas rats develop mammary tumors only after exposures to 1000-8000 ppm BD. Extensive research has been carried out to determine where humans fit into this susceptibility range. Species differences in rates of metabolism of BD have been noted, but inconsistencies in metabolism data from different laboratories and some problems in the fit of physiologically based pharmacokinetic (PBPK) models with experimental data have left uncertainties. The experiments reported here are intended to clarify the issue of human metabolism of BD and to determine if metabolism of BD in cynomolgus monkeys is similar enough to metabolism in humans to use in vivo data from monkeys for PBPK modeling. The results indicate that for the reactions studied (oxidation of BD to the mono- and diepoxide), BD is metabolized substantially the same in monkey and human hepatic microsomes. The human metabolism data agreed with that reported earlier when the in vitro metabolism of BD was studied at low BD concentrations. Finally, BD at high concentrations was found to inhibit the further oxidation of its metabolite, the monoepoxide. Incorporation of this information on the competition between BD and its first oxidation product for CYP2E1 should improve the fit of PBPK models.     

Impact of Multifocality and Multilocation of Positive Surgical Margin After Radical Prostatectomy on Predicting Oncological Outcome

Objective

To assess the impact of focality and location of positive surgical margins (PSM) on long-term outcomes after radical prostatectomy (RP) for prostate cancer (PCa), including biochemical recurrence (BCR), metastasis and overall mortality.

Faecal calprotectin and lactoferrin as markers of acute radiation proctitis: a pilot study of eight stool markers

BACKGROUND: Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available. The faecal excretion of eight markers of gut inflammation was therefore examined. Five proteins and three lipid derivates were analysed in sequential stool samples taken before and during radiation therapy. METHODS: Stool samples from 15 patients with prostate cancer scheduled for radiation therapy were examined. Pretreatment and in-treatment samples (2nd and 6th weeks) were measured by enzyme-linked immunosorbent assay (ELISA) (calprotectin, lactoferrin, transferrin, leukotriene B4, prostaglandin E2, thromboxane B2 and TNF alpha) or nephelometry (alpha 1-antitrypsin). RESULTS: Calprotectin and lactoferrin concentrations increased significantly during radiation treatment (P = 0.0005 and P = 0.019). Transferrin was detected in only 9 out of 45 samples. There were no changes in tumour necrosis factor alpha (TNF alpha), leukotriene B4, prostaglandin E2 and thromboxane B2 during treatment. alpha 1-antitrypsin could not be detected in any sample. CONCLUSIONS: This study indicates that faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis. Patient compliance and stability of the markers make this a promising method for clinical research. Eicosanoids could be measured in stool samples, but the concentrations did not increase with increasing radiation dose.