Drug metabolizing enzyme system and heme pathway in hepatocarcinogenesis.
Chemically induced and spontaneous liver tumors share some metabolic alterations. The decline in hemoprotein levels during hepatocarcinogenesis may result from a diminution of the intracellular heme pool. To elucidate if the onset of the pre-initiation stage alters the natural regulation mechanism of heme pathway, animals were fed with p-dimethylaminoazobenzene (DAB) and treated or not with 2-allylisopropylacetamide (AIA). The induction of 6-Aminolevulinic acid synthase (ALA-S) activity and the diminution in microsomal heme oxygenase (MHO) did not change when DAB fed animals were treated with AIA. Cytochrome P-450 (P-450) levels and glutathione S-transferase activity were increased in all the groups tested. Tryptophan pyrrolase, sulphatase and beta-glucuronidase activities were altered in DAB fed animals but AIA treatment did not produce any effect. Changes in drug metabolizing enzymes in livers of DAB fed animals could be the result of a primary deregulation of heme metabolism. These results give additional support to our hypothesis about a mechanism for the onset of hepatocarcinogenesis.
Vazquez
E
E
Centro de Investigaciones sobre Porfirinas y Porfirias, (CONICET-FCEN, UBA), Cuidad Universitaria, Pabellón II, Buenos Aires, Republica Argentina.
Gerez
E
E
Caballero
F
F
Polo
C
C
Batlle
A
A
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000502:Allylisopropylacetamide / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005966:Glucuronidase / Q000172:deficiency / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006420:Hemeproteins / Q000172:deficiency* / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D010084:Oxidation-Reduction; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000633:toxicity; D013429:Sulfatases / Q000172:deficiency / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism; D004124:p-Dimethylaminoazobenzene / Q000493:pharmacokinetics* / Q000633:toxicity
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006420:Hemeproteins; D011355:Prodrugs; D000502:Allylisopropylacetamide; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D014366:Tryptophan Oxygenase; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D005982:Glutathione Transferase; D013429:Sulfatases; D005966:Glucuronidase