Modulation of P-450 IIC7 and IIIA1,2 mRNA in pre-neoplastic liver. Effect of promotion by phenobarbital.
P-450 IIC7 and IIIA2 mRNAs are constitutively expressed in the hepatic tissue under developmental control. Both forms--as well as IIIA1, 90% homologous to IIIA2 mRNA--display positive modulation by phenobarbital a prototype inducer of the liver monooxygenases and a strong promoter of experimental chemical hepatocarcinogenesis. In the present work the variations in the concentration of these P-450 mRNA were studied in rats submitted to the hepatocarcinogenic protocol of Solt and Farber. We demonstrate that a decrease in the relative concentrations of P-450 IIC7 and IIIA1, 2 mRNA is set up along the tumor promotion stage. Animals--starting the experimental carcinogenic protocol at pubertal age--show a partial inhibition of the physiological expression of P-450 IIIA1,2 mRNA associated to male sex maturation. Administration of phenobarbital results in an acceleration of the pre-neoplastic process which is concomitant with an induction of P-450 IIC7 as well as IIIA1,2 at the earlier promotion stages. P-450 mRNA concentration markedly decreases as the preneoplastic process develops. While an impaired P-450 IIIA1,2 mRNA relative abundance is observed, an inversion of the modulation of P-450 IIC7 as well as of the male phenotype marker alpha-2u-globulin mRNA arises as the tumor promotion stage progresses, both mRNA becoming repressed in response to phenobarbital.
Laboratório de Bioquímica, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
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MC
Lechner
M
M
Barroso
F
F
Decloitre
C
C
Lafarge-Frayssinet
M
M
Ouldelhkim
C
C
Frayssinet
D000510:Alpha-Globulins / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D010641:Phenotype; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D051381:Rats; D000509:alpha-Fetoproteins / Q000235:genetics
D000510:Alpha-Globulins; D002273:Carcinogens; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C013803:alpha 2u globulin; D000509:alpha-Fetoproteins; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital