Characterization of the cytochrome P450 isozyme that metabolizes ochratoxin A, using metabolic inducers, inhibitors and antibodies.
The phenotypic pattern of drug biotransformation is determined by both host and environmental factors. Debrisoquine is a good probe for phenotyping individuals, as its metabolism is not affected by age, gender, smoking habits or alcohol intake. People with Balkan endemic nephropathy or with urinary tract tumours in endemic areas are more frequently extensive metabolizers of debrisoquine than are healthy people. This finding has led to studies of the possible relationship between the metabolism of ochratoxin A and its toxicity and carcinogenicity on experimental models. Ochratoxin A is metabolized mainly in the liver into R- and S-isomers of 4- and 10-hydroxyochratoxin A, and the reaction is catalysed by cytochrome P450 haemoprotein. Animal species that are genetically different in their capacity to metabolize debrisoquine differ similarly in their capacity to metabolize ochratoxin A: female DA rats that are poor metabolizers of debrisoquine also poorly metabolize ochratoxin A, as assayed by urinary excretion of both the parent compound and of 4-hydroxyochratoxin A. Ochratoxin A hydroxylase activity is low in DA rat liver (and kidney) but is inducible by phenobarbital and 3-methylcholanthrene; debrisoquine hydroxylase is not known to be inducible by enzyme inducers. The reaction of ochratoxin A hydroxylase thus resembles those induced by 3-methyl-cholanthrene and catalysed by cytochrome P450IA. Ochratoxin A hydroxylase activity was further characterized in the livers of B6 and D2 mice that had been treated with typical enzyme inducers. Ochratoxin A hydroxylase was weakly inducible by phenobarbital, 3-methyl-cholanthrene and 2,4,7,8-tetrachlorodibenzodioxin.(ABSTRACT TRUNCATED AT 250 WORDS)
Hietanen
E
E
Department of Clinical Physiology, University of Turku, Finland.
Bartsch
H
H
Béréziat
J C
JC
Castegnaro
M
M
Michelon
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001571:Benzoflavones / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009793:Ochratoxins / Q000493:pharmacokinetics*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000276:immunology; D010641:Phenotype; D011110:Polymorphism, Genetic
D000911:Antibodies, Monoclonal; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009793:Ochratoxins; C025589:ochratoxin A; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; C043872:bufuralol 1'-hydroxylase; C075477:ochratoxin A hydroxylase; D008797:Metyrapone