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The distributions of glycogen phosphorylase, hexokinase, phosphofructokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase, citrate synthase, malate dehydrogenase, beta-hydroxyacyl CoA dehydrogenase, and adenylokinase were determined in the mudpuppy retina. Distinct differences were found in regard to the glycolytic and oxidative capacities of the various layers. In the outer retina, citric acid cycle enzymes were high while glycolytic enzymes were low. Synaptic zones were distinctly enriched in all energy-producing enzymes. Mudpuppy photoreceptors were found to be rich in phosphorylase but poor in glucose-6-phosphate dehydrogenase, suggestive of some evolutionary divergence from mammals in the metabolic machinery which is used to support the visual process.

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The activity of glucose-1,6-bisphosphatase and the level of its substrate were measured in 16 gray areas and four fiber areas of mouse brain and 10 layers or sublayers of monkey retina. Because of the low activity of the enzyme and the small sample sizes, it was necessary to develop a method with two different amplification steps (overall amplification about 10(6]. The enzyme ranged in activity 100-fold from a low in monkey retina photoreceptor cells to a high in the pyramidal layer of the hippocampus. However, in gray areas of the brain proper the range was only about fourfold. This, together with its requirement for IMP, suggests that the enzyme has a widespread metabolic function related to states of increased neuronal activity. Glucose-1,6-bisphosphate levels varied from 80 to 960 mu mol/kg dry weight in different areas of mouse brain and from 44 to 200 mu mol/kg dry weight in different layers of monkey retina. In general, the glucose bisphosphate levels correlated positively with the bisphosphatase activities; however, the three areas with the highest enzyme concentrations did not fit this pattern.

Introduction Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. Objective We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer. Results Among the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. Conclusions These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.