A spectrofluorometric assay for the estimation of the tremorgenic mycotoxin verruculogen in crude mycelial extract has been devised and used to determine concentrations as low as 0.2 microgram ml-1. Verruculogen production by Penicillium estinogenum has been extended from surface culture to submerged culture in 60 1 stirred fermenters, in which the maximum cell-associated mycotoxin yield [5 mg (100 ml culture)-1] was obtained within 7 d. It was found necessary to supplement the medium (Czapek Dox broth plus 0.5% yeast extract) with calcium chloride (2%) to induce profuse sporulation (2 X 10(7) conidia ml-1).
In surface culture of Penicillium simplicissimum, verruculogen was shown to be biosynthesized from the intact carbon skeletons of tryptophan and proline, isoprenoid derivatives of mevalonic acid, and a methyl group donated by methionine. Selected radiolabeled precursors (1 mCi) pulse-fed at the optimum stage of fermentation yielded verruculogen (specific activity, 5.89 x 102 ,XCi mmol-1) labeled in the prolyl and isoprenyl regions of the molecule and suitable for metabolic studies. Verruculogen was first isolated from Penicillium verruculosum (2), and its structure (Fig. 1) has been determined (1, 6). As the most potent tremorgenic mycotoxin known, its possible role,
Two new indolic metabolites were isolated from Penicillium crustosum and separated from other penitrem mycotoxins by high-performance liquid chromatography. Penitrem D is a deoxy-penitrem A. Penitrem E is dechloro-penitrem A and was shown to be tremorgenic in mice, although it has only one-third of the activity of penitrem A. Roquefortine was also shown, for the first time, to be an important metabolic product of P. crustosum.
Radiolabeled verruculogen was detected in a wide range of body tissues 6 min after intravenous administration, but after a further 20 min it was mainly being excreted via the biliary route. In isolated liver perfusion, [14C]verruculogen was rapidly taken up by the liver and metabolized completely, principally to the related tremorgen TR-2 but also to a desoxy derivative of verruculogen. In addition, a smaller amount of an isomer of TR-2 was detected. These metabolic products were excreted in the bile.
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