title: Disruption of sphingolipid biosynthesis in hepatocyte nodules: selective proliferative stimulus induced by fumonisin B1.
abstract: In order to investigate the role of sphingolipid disruption in the cancer promoting potential of fumonisin B(1) (FB(1)) in the development of hepatocyte nodules, male Fischer 344 rats were subjected to cancer initiation (FB(1) containing diet or diethylnitrosamine (DEN) by i.p. injection) and promotion (2-acetylaminofluorene with partial hepatectomy, 2-AAF/PH) treatments followed by a secondary FB(1) dietary regimen. Sphinganine (Sa) and sphingosine (So) levels were measured by high performance liquid chromatography in control, surrounding and nodular liver tissues of the rats. The disruption of sphingolipid biosynthesis by the secondary FB(1) treatment in the control rats was significantly (P < 0.05) enhanced by the 2-AAF/PH cancer promotion treatment. The nodular and surrounding Sa levels returned to baseline following FB(1) initiation and 2-AAF/PH promotion. When comparing the groups subjected to the secondary FB(1) treatment, the initiation effected by FB(1) was less (P < 0.01) sensitive to the accumulation of Sa in the nodular and surrounding tissues than DEN initiation and the 2-AAF/PH control treatment. In contrast, the So level of FB(1) initiation was marginally increased in the nodules compared to the surrounding liver after 2-AAF/PH promotion and significantly (P < 0.05) higher with the secondary FB(1) treatment. Although, the FB(1)-induced hepatocyte nodules were not resistant to the disruption of sphingolipid biosynthesis, the nodular So levels were increased and might provide a selective growth stimulus possibly induced by bio-active sphingoid intermediates such as sphingosine 1-phosphate (S1P).
authors.affiliation: Programme on Mycotoxins and Experimental Carcinogenesis Unit, Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa. liana.van.der.westhuizen@mrc.ac.za
authors.forename: Liana
authors.initials: L
authors.lastname: van der Westhuizen
authors.forename: Wentzel C A
authors.initials: WC
authors.lastname: Gelderblom
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Shephard
authors.forename: Sonja
authors.initials: S
authors.lastname: Swanevelder
mesh_terms: D000818:Animals; D037341:Fumonisins / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013107:Sphingolipids / Q000096:biosynthesis*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D013723:Teratogens / Q000633:toxicity*
chemical_list: D037341:Fumonisins; D013107:Sphingolipids; D013723:Teratogens; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013110:Sphingosine; C005682:safingol