Interstrain comparison of hepatic and renal microsomal carcinogen metabolism and liver S9-mediated mutagenicity in DA and Lewis rats phenotyped as poor and extensive metabolizers of debrisoquine.
Lewis (extensive metabolizers) and DA (poor metabolizers) rat strains show genetic polymorphism for the gene regulating debrisoquine 4-hydroxylation in a manner analogous to human drug polymorphism and show also a different toxicological response to aflatoxin B1. In order to investigate the underlying mechanism(s) of the different drug-metabolizing capacities, the in vitro metabolism and liver S9-mediated mutagenicity of several drugs and carcinogens were studied in female Lewis and DA rat strains, using untreated, 3-methylcholanthrene-treated, and phenobarbital-treated animals. S9-mediated mutagenicity of aflatoxin B1 and hepatic and renal ochratoxin A 4-hydroxylase activity were much lower in DA rats; however, the activity of a number of other hepatic and renal drug-metabolizing enzymes did not show any interstrain difference. Slight strain differences were found in the inducibility of several hepatic drug-metabolizing enzymes, except for ochratoxin A 4-hydroxylase activity; the latter was inducible only by 3-methylcholanthrene in the DA strain and appeared to be linked genetically with other Ah locus-associated monooxygenases. Our data suggest that ochratoxin A 4-hydroxylase activity, which is low in the DA strain, is catalyzed by a cytochrome P-450 isozyme different from that responsible for debrisoquine 4-hydroxylation. Our results provide some insight into why the two metabolic oxidation phenotypes show different susceptibility to cancer induction and to the toxicity of certain environmental carcinogens, such as aflatoxin B1 and ochratoxin A.
Hietanen
E
E
Malaveille
C
C
Camus
A M
AM
Béréziat
J C
JC
Brun
G
G
Castegnaro
M
M
Michelon
J
J
Idle
J R
JR
Bartsch
H
H
D015073:2-Acetylaminofluorene / Q000378:metabolism; D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism; D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003647:Debrisoquin / Q000378:metabolism*; D004101:Dihydroxydihydrobenzopyrenes; D005260:Female; D014453:Glucuronosyltransferase / Q000032:analysis; D006900:Hydroxylation; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism; D009793:Ochratoxins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010641:Phenotype; D011506:Proteins / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D013045:Species Specificity
D000348:Aflatoxins; D001580:Benzopyrenes; D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; D007546:Isoquinolines; D009153:Mutagens; D009602:Nitrosamines; D009793:Ochratoxins; D004364:Pharmaceutical Preparations; D011506:Proteins; C017228:benzo(a)pyrene 7,8-dihydrodiol; C002741:N-nitrosomorpholine; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1; D014453:Glucuronosyltransferase; D003647:Debrisoquin; D010634:Phenobarbital