Chromatographic Fractionation of Penicillium polonicum Fermentation Metabolites in Search of the Nephrotoxin(s) for Rats

Complex renal histopathological changes in rats, in silent response to dietary contamination with wheat moulded by a common Penicillium from the Balkans, have long eluded attribution of a causal toxin. So far, water-soluble amphoteric glyco-peptides seem responsible, at least for the nuclear pyknoses in nephron epithelia after several days of dietary exposure. Recently, refined histology analysis has diagnosed pyknosis as apoptosis, and followed the finding through application of medium-pressure liquid chromatography, anion exchange and silica layer chromatography to fractionate a water/alcohol-soluble extract of a fungal fermentation on wheat. Proline was revealed, with other amino acids, in acid hydrolysate of the fermentation extract. Application of mass spectrometry has recognized prominent ions (m/z 550 and 564) correlated with fragmentations consistent with a terminal proline moiety for the putative toxins, coupled with other structural fragments and correlated with apoptosis. Use of 14C-proline in probing Penicillium polonicum fermentation to aid isolation of the new potential toxins, along with application of gel electrophoresis, may further aid characterization of the apoptosis toxin(s). The present focus on proline peptides in mycotoxicosis fits easily with their increasingly recognised pharmacological activity associated with proline’s rigid secondary amine structure, which causes conformational contortion in peptides. Nevertheless, there remains the striking rat renal karyocytomegaly by P. polonicum, for which there is yet no causative mycotoxin.

[1]  A. Miljković,et al.  Renal Apoptosis in the Mycotoxicology of Penicillium polonicum and Ochratoxin A in Rats , 2022, Life.

[2]  Hu Li,et al.  Ochratoxin A induces nephrotoxicity in vitro and in vivo via pyroptosis , 2021, Archives of Toxicology.

[3]  M. Misiura,et al.  Proline‐containing peptides—New insight and implications: A Review , 2019, BioFactors.

[4]  P. Mantle,et al.  Purpurolic acid: A new natural alkaloid from Claviceps purpurea (Fr.) Tul. , 2016, Fungal biology.

[5]  P. Mantle,et al.  Contribution of Organ Vasculature in Rat Renal Analysis for Ochratoxin A: Relevance to Toxicology of Nephrotoxins , 2015, Toxins.

[6]  A. Vitali Proline-Rich Peptides: Multifunctional Bioactive Molecules As New Potential Therapeutic Drugs. , 2015, Current protein & peptide science.

[7]  T. Yano,et al.  Mitochondrial superoxide production contributes to vancomycin-induced renal tubular cell apoptosis. , 2012, Free radical biology & medicine.

[8]  J. Fincham,et al.  Contrasting Nephropathic Responses to Oral Administration of Extract of Cultured Penicillium polonicum in Rat and Primate , 2010, Toxins.

[9]  M. Dutton,et al.  Complex etiology and pathology of mycotoxic nephropathy in South African pigs , 2010, Mycotoxin Research.

[10]  S. H. Koch,et al.  Contamination with storage fungi of human food from Cameroon. , 2009, International journal of food microbiology.

[11]  S. H. Koch,et al.  Identification of novel metabolite and its cytotoxic effect on human lymphocyte cells in comparison to other mycotoxins , 2009 .

[12]  J. Nagy,et al.  Binding of Ochratoxin A to a Urinary Globulin: A New Concept to Account for Gender Difference in Rat Nephrocarcinogenic Responses , 2008, International journal of molecular sciences.

[13]  L. Collinson,et al.  A radiochemical technique with potential for revealing novel fungal metabolites according to expression of specific biosynthetic activities. , 2008, Mycological research.

[14]  S. Çelik,et al.  Protective effects of caffeic acid phenethyl ester, vitamin C, vitamin E and N-acetylcysteine on vancomycin-induced nephrotoxicity in rats. , 2007, Basic & clinical pharmacology & toxicology.

[15]  J. B. Greig,et al.  Nephrotoxicity of Penicillium aurantiogriseum, a possible factor in the aetiology of Balkan Endemic Nephropathy , 1988, Mycopathologia.

[16]  J. Frisvad,et al.  Mycotoxins, drugs and other extrolites produced by species in Penicillium subgenus Penicillium , 2004 .

[17]  P. Mantle,et al.  Persistent karyomegaly caused by Penicillium nephrotoxins in the rat , 1991, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[18]  P. Mantle,et al.  Acute histopathological changes produced by Penicillium aurantiogriseum nephrotoxin in the rat. , 1991, International journal of experimental pathology.

[19]  J. B. Greig,et al.  Comparative acute nephrotoxicity of Penicillium aurantiogriseum in rats and hamsters. , 1991, IARC scientific publications.

[20]  A. Bendele,et al.  Ochratoxin A carcinogenesis in the (C57BL/6J X C3H)F1 mouse. , 1985, Journal of the National Cancer Institute.

[21]  P. Krogh Casual associations of mycotoxic nephropathy. , 1978, Acta pathologica et microbiologica Scandinavica. Supplement.

[22]  F. Flynn,et al.  BALKAN (ENDEMIC) NEPHROPATHY AND A TOXIN-PRODUCING STRAIN OF PENICILLIUM VERRUCOSUM VAR CYCLOPIUM: AN EXPERIMENTAL MODEL IN RATS , 1977, The Lancet.

[23]  P. Austwick Comparative Aspects of Renal Disease , 1975 .

[24]  P. Mantle,et al.  Metabolic studies on Claviceps purpurea during parasitic development on rye. , 1974, Journal of general microbiology.

[25]  H. Bartsch,et al.  International Agency for Research on Cancer. , 1969, WHO chronicle.

[26]  L. Fourie,et al.  Ochratoxin A, a Toxic Metabolite produced by Aspergillus ochraceus Wilh. , 1965, Nature.