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Bovine oocytes were collected from ovaries obtained from an abattoir. They were classified according to the character of the cumulus cells using a stereomicroscope, and cultured in 25 mM Hepes buffered Tissue Culture Medium 199 supplemented with 10% fetal calf serum at 39 degrees C and inseminated by capacitated sperm. Maturation rates of Class A oocytes, with compact, dense cumulus cells; Class B, partially naked oocytes with thin cumulus layers or small remnants of cumulus cells and Class C, naked oocytes were 97.4% (38/39), 89.8% (106/118) and 52.9% (45/85), respectively. The fertilization rates for the three classes were 86.8%, 85.8% and 53.3%, respectively. The naked oocytes had a significantly lower fertilization rate than oocytes of the other two classes. Significantly more Class A oocytes cleaved (63.7%, 232/364) than those of Class B (29.5%, 36/122) and Class C (17.7%, 28/158).
Pure orellanine, a nephrotoxic compound extracted from the mushroom Cortinarius orellanus, which is known to induce severe kidney damage several days or weeks after ingestion, is found to inhibit strongly the synthesis of macromolecules (proteins, RNA and DNA) in Madin-Darby canine kidney (MDCK) cells and in rat liver mitochondria, although the uptake of labelled precursors of the above macromolecules is not significantly altered. Direct addition of orellanine to a cell-free system of rabbit reticulocyte lysate does not produce any inhibition of protein synthesis. However, when orellanine is pre-incubated with activating rat liver microsomal systems, this inhibition occurs. Thus, the in vivo inhibition of protein synthesis is most likely due to a metabolite of orellanine.
Drugs possessing a carboxylate functional group usually form acyl glucuronides as major metabolites. These electrophilic metabolites can undergo several spontaneous reactions, including covalent adduct formation with proteins. The present study examined whether covalent adducts were formed with microtubular protein (MTP, 85%, alpha/beta-tubulin) and whether this influenced its ability to assemble into microtubules. Bovine brain microtubular protein (MTP) was purified by assembly-disassembly cycles and incubated with the nonsteroidal anti-inflammatory drug (NSAID) zomepirac (ZP), its acyl glucuronide (ZAG) and rearrangement isomers (iso-ZAG) at various concentrations for 2 h at room temperature and pH 7.5. Assembly was monitored by change in turbidity (increase in absorbance at 340 nm). Both ZAG and iso-ZAG caused dose-dependent inhibition of assembly (50% inhibition at about 1 mM), while ZP caused modest inhibition (< 50% inhibition at 4 mM). In a slightly different system, incubation of performed microtubules with 4 mM ZAG caused about 35% inhibition of reassembly ability, while modification of MTP under similar conditions resulted in about 85% reduction of assembly ability. Immunoblotting with a ZP antiserum showed that ZAG and iso-ZAG covalently modified MTP in a dose-dependent manner, while ZP itself caused no modification. Tubulin and many minor proteins comprising MTP were modified. ZP-modified tubulin was shown to be present in the cytosol of livers from rats dosed twice daily for 3 days with ZP at 50 mg/kg, using a sandwich ELISA with ZP and tubulin antisera. Whether any perturbation of microtubule assembly occurs in vivo as a result of this in vivo modification is currently under investigation.
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Water containing hydrophilic ointment DAB 1997 was modified by the incorporation of ethanol and the effects of ethanol on the evaporation, the drug liberation and the permeation through human excised stratum corneum were investigated. Creams with 10%, 20%, 30% (v/v) and without ethanol were produced. As a model drug 2% (w/w) hydrocortisone-21-acetate was suspended in the o/w cream. The evaporation of the creams decreased with an increasing amount of ethanol which was unexpected because the vapor pressure of ethanol is higher than that of water. From this result it was concluded that ethanol might be interlamellarly fixed in the mixed crystal of the polyhydrate of the emulsifier to a higher extent than it is distributed within the aqueous bulk phase. In context with the liberation studies, ethanol decreased the drug liberation from the cream. This is in accordance with the above hypothesis of the ethanol partitioning within the cream, because the solubility of the drug in ethanol is higher than that in water. Therefore the interlamellar drug concentration should be higher than the solubility of the drug in the bulk phase, with the assumption that the gel network of the emulsifier polyhydrate is finally responsible for the delay in drug liberation. The permeation through stratum corneum showed no significant differences between the alcohol-free and the alcohol-loaded formulations. Obviously the decrease in drug liberation by ethanol was compensated for by the penetration enhancing effect.