Altered expression of cytochrome P450 and possible correlation with preneoplastic changes in early stage of rat hepatocarcinogenesis.
OBJECTIVE
Correlation of cytochrome P450 (CYPs) with preneoplastic changes in the early stage of hepatocarcinogenesis is still unclear. To detect the expression of carcinogen-metabolizing related microsomal P450 enzymes, namely the CYP1A1, CYP1A2, CYP2B1/2, CYP2E1, and CYP3A, we performed the medium-term bioassay of Ito's model in Sprague-Dawley rats.


METHODS
The amount and activity of CYP were assessed by biochemical and immunohistochemical methods in week 8. The correlation between CYP expression and microsomal oxidative stress was investigated by comparing the generation of microsomal lipid peroxidation in the presence or absence of specific CYP inhibitor.


RESULTS
In the DEN-2-AAF and 2-AAF alone groups, the expression of CYP1A1 and CYP2E1 were up-regulated and the expression of CYP2B1/2 and CYP1A2 were quite the contrary. Strong staining of CYP2E1 and CYP2B1/2 was found around the centrolobular vein and weak staining in the altered hepatic foci revealed by immunohistochemical procedure. There was no significant change in the activity of CYP3A among the 4 groups. Altered hepatic tissue bore more microsomal NADPH (nicotinamide adenine dinucleotide phosphate,reduced form)-dependent lipid peroxidation than normal tissue. And the difference among the 4 groups disappeared when CYP2E1 was inhibited. More microsomal lipid peroxidation was generated when incubated with CYP1A inhibitor a-naphthoflavone.


CONCLUSIONS
CYP altered their expression levels and these alterations can play important roles in the alteration of cell redox status of preneoplastic tissue in the early stage of hepatocarcinogenesis.
Liu
Lin-lin
LL
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Gong
Li-kun
LK
Qi
Xin-ming
XM
Cai
Yan
Y
Wang
Hui
H
Wu
Xiong-fei
XF
Xiao
Ying
Y
Ren
Jin
J
D015073:2-Acetylaminofluorene; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002273:Carcinogens; D003043:Cocarcinogenesis; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004052:Diethylnitrosamine; D004050:Ditiocarb / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001571:Benzoflavones; D002273:Carcinogens; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004052:Diethylnitrosamine; D008315:Malondialdehyde; C011512:alpha-naphthoflavone; D004050:Ditiocarb; D015073:2-Acetylaminofluorene; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1