Liver injury and expression of cytochromes P450: evidence that regulation of CYP2A5 is different from that of other major xenobiotic metabolizing CYP enzymes.
The purpose of this study was to find out how liver injury caused by two well-known hepatotoxins, chloroform and thioacetamide, alters the expression of hepatic xenobiotic metabolizing cytochrome P450 (CYP) enzymes of DBA/2N mice. Dose-dependent toxic effects of the two hepatotoxins were verified by histological examination. Along with the toxicity, intense staining of immunoreactive material was detected in the centrilobular zone, with anti-CYP2A5 antibody in hepatic tissue. This apparent increase in the expression of Cyp2a-5 was verified by Northern blot and Western blot analyses and by determining the enzymatic activity, coumarin 7-hydroxylase, in hepatic tissue. The results suggest that liver injury due to these hepatotoxins increases the expression of Cyp2a-5 and that the expression is pretranslationally regulated. The increased expression of Cyp2a-5 is in contrast with that of other xenobiotic metabolizing CYPs because a dose-[dose-dependent] dependent decrease of the total hepatic P450 content and either a decrease or no change in the levels of CYP1A, 2B, 2C, 2E1, and 3A4 were observed. The results suggest that essential differences exist in the regulation of CYP2A5 and other major xenobiotic metabolizing CYP enzymes and that in a damaged liver CYP2A5 may be a major catalyst of xenobiotic metabolism.
Camus-Randon
A M
AM
International Agency for Research on Cancer, Lyon, France.
Raffalli
F
F
Béréziat
J C
JC
McGregor
D
D
Konstandi
M
M
Lang
M A
MA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002725:Chloroform / Q000633:toxicity*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity; D013853:Thioacetamide / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism*
D002273:Carcinogens; D011720:Pyrazoles; D015262:Xenobiotics; D013853:Thioacetamide; C031280:pyrazole; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2