Overexpression of a cytochrome P-450 of the 2a family (Cyp2a-5) in chemically induced hepatomas from female mice.
Chemical hepatocarcinogenesis in female mice, induced by 5,9-dimethyl(7H)dibenzo[c,g]carbazole, leads to the overexpression of a cytochrome P-450 of the 2a family. This protein was identified as Cyp2a-5, by the use of immunoblots obtained from isoelectric focusing gels. This method allowed the distinction of Cyp2a-5 from Cyp2a-4, another mouse liver cytochrome P-450, by taking advantage of their slightly different pI values. The theoretical pI values, determined from the amino acid sequence, were pI 9.91 for Cyp2a-4 and pI 10.01 for Cyp2a-5. Other structurally related forms were not detected. In hepatomas from female mice, only the Cyp2a-5 form was overexpressed (2-3 fold). Male mice showed a weak expression of Cyp2a-4 and Cyp2a-5 in control liver samples and in hepatomas. The expression of both forms was increased more than fivefold upon castration. Pyrazole induces specifically the Cyp2a-5 form. The Cyp2a-5 overexpression was correlated with enhanced microsomal coumarin-7-hydroxylase and testosterone-15 alpha-hydroxylase activities. An immunohistochemical study showed that Cyp2a-4 and Cyp2a-5 are expressed uniformly in female livers, but centrilobularly in male livers. In hepatomas, this localisation is perturbed; in females we observed a focal cell localisation, and the Cyp2a-containing cells were often hypertrophic and polyploid. In hepatomas from male mice, the Cyp2a-containing cells became dispersed. From a comparison with other studies, the Cyp2a-5 overexpression appears to be a general feature of hepatocarcinogenesis in mice.
Jounaïdi
Y
Y
Institut National de la Santé et de la Recherche Médicale, Unité 128, Montpellier, France.
Bonfils
C
C
Périn
F
F
Negishi
M
M
Lange
R
R
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002227:Carbazoles; D002273:Carcinogens; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007525:Isoelectric Focusing; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000378:metabolism
D002227:Carbazoles; D002273:Carcinogens; C039387:5,9-dimethyldibenzo(c,g)carbazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; C022724:testosterone 7-alpha-hydroxylase, hamster