The effects of the tremorgenic mycotoxin penitrem A on the rat cerebellum.

Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg), rats develop severe generalized tremors and ataxia that persist for up to 48 hours. These are accompanied by a three- to fourfold increase in cerebellar cortical blood flow. Mitochondrial swelling occurs in cerebellar stellate and basket cells within 30 minutes of dosing and persists for more than 12 hours without leading to cell death. From 2 hours, Purkinje cell dendrites show early cytoplasmic condensation accompanied by fine vacuolation of smooth endoplasmic reticulum and enlargement of perikaryal mitochondria. From 6 hours, many Purkinje cells develop intense cytoplasmic condensation with eosinophilia that resembles "ischemic cell change," and from 12 hours, many other Purkinje cells show marked watery swelling. Astrocytes begin to swell from 0.5 hours after injection and show hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci of necrosis appear in the granule cell layer, while permeability of overlying meningeal vessels to horseradish peroxidase becomes evident at 8 hours. All changes are more severe in vermis and paravermis. Despite widespread loss of Purkinje cells, the animals' behavior becomes almost normal within a week. While tremor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minimal. The tremor mechanism differs from that of harmaline since destruction of inferior olivary nuclei abolishes neither the tremor response to penitrem A nor the cellular damage. No morphological changes are found in other brain regions. The affinities of penitrem A for high-conductance calcium-dependent potassium channels and for gamma-aminobutyric acid receptors with the probability of resultant excitotoxity are considered to be important underlying factors for these changes.

Distribution of xenobiotic metabolizing enzymes in skin.

In the present study, the distribution and nature of specific xenobiotic-metabolizing enzymes has been studied. Immunocytochemistry revealed the specific isoenzyme profile of the different cell types in mouse, rat and human skin. Constitutive levels of cytochrome P-450 1A1/A2 (CYP1A1/A2), CYP2B1/B2 and glutathione S-transferase were concentrated in the epidermis and sebaceous glands of all three species. Enzymic digestion followed by density gradient centrifugation resulted in fractions enriched in sebaceous cells, basal cells and differentiated keratinocytes. The basal and sebaceous cells of mouse skin were found to contain high levels of CYP1A1/A2, which was induced approximately 10-fold following beta-naphthoflavone pretreatment. These findings suggest that xenobiotic metabolizing enzymes exhibit a similar qualitative distribution between the cell types of rodent and human skin and that these cell types may be isolated for use in mechanistic studies involving cutaneous metabolism and toxicity.