Heme biosynthesis pathway regulation in a model of hepatocarcinogenesis pre-initiation.
1. Heme regulation before the appearance of hyperplastic nodules was investigated in mice models of hepatocarcinogenesis. 2. With this aim 5-aminolaevulinate synthetase (ALA-S), microsomal heme-oxygenase (MHO), mitochondrial and cytoplasmic rhodanese activities were examined throughout a period of 35 days in animals exposed to dietary p-dimethylaminoazobenzene (DAB). 3. ALA-S activity was significantly diminished (50%) on day 14, then showing a sharply rising profile from day 28 onwards, and reaching 350% on day 35. 4. A similar profile was observed for mitochondrial rhodanese activity. 5. Changes in MHO and cytoplasmic rhodanese activities were almost the opposite to those observed for ALA-S. 6. The distinctive alteration in mitochondrial and cytoplasmic rhodanese would suggest that it plays a subtle role in ALA-S regulation during carcinogenesis initiation through a mechanism that appears to involve subcellular localization controls perhaps by means of the breakage of cystine trisulphide postulated to act as an ALA-S activator. 7. Taking into account the present results, we suggest a probable mechanism for the onset of hepatocarcinogenesis that includes a primary activating liver status, provoking biochemical aberration leading to the stage of initiation of hepatocarcinogenesis involving the whole organ.
Polo
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CF
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET y FCEN, UBA, Ciudad Universitaria, Republic of Argentina.
Vazquez
E S
ES
Caballero
F
F
Gerez
E
E
Battle
A M
AM
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000201:enzymology; D006418:Heme / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D013884:Thiosulfate Sulfurtransferase / Q000378:metabolism; D004124:p-Dimethylaminoazobenzene
D006418:Heme; D004124:p-Dimethylaminoazobenzene; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D013884:Thiosulfate Sulfurtransferase