Cytochrome P450 induction and mutagenicity of 2-aminoanthracene (2AA) in rat liver and gut.
The aim of our study was to establish a relationship between the ability of rat liver and gut to activate 2-aminoanthracene (2AA) into mutagens and their P450 enzyme composition. Rats were orally pretreated with beta-naphthoflavone (beta NF), phenobarbital (PB), dexamethasone (DEX) or acetone (AT). Mutagenic activation of 2AA was detected in the Ames test. P450IA1, IA2, IIB1/B2 and IIE1 were immunochemically quantified by Western blots. All the results were compared to those obtained in untreated rats. In all tissues, beta NF treatment considerably increased the mutagenicity of 2AA. PB treatment significantly reduced the mutagenicity of 2AA in the liver but not in the intestine. By contrast, AT treatment significantly decreased the number of revertants in the duodenum but not in the liver whereas DEX treatment significantly decreased the number of revertants in both tissues. 2AA appears to be metabolized by various P450s in both organs. In the liver, reactive metabolites may be produced after metabolism by the P450IA subfamily. The other P450 enzyme seems to play a part in the metabolism of 2AA leading to formation of either mutagenic or non-mutagenic metabolites.
Carrière
V
V
Inserm U75, Paris, France.
de Waziers
I
I
Courtois
Y A
YA
Leroux
J P
JP
Beaune
P H
PH
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000378:metabolism / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D015153:Blotting, Western; D003106:Colon / Q000201:enzymology / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D007421:Intestine, Small / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D019324:beta-Naphthoflavone
D000873:Anthracenes; D001571:Benzoflavones; D009153:Mutagens; D000096:Acetone; D019324:beta-Naphthoflavone; D003907:Dexamethasone; C006593:2-anthramine; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital