Inhibitor panel studies of human hepatic and placental cytochrome P-450-associated monooxygenase activities.
1. A panel of nine inhibitors displaying some P-450 isozyme specificity was used to characterize aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin 0-deethylase (ERDE) activities in human liver and placenta in vitro in comparison with liver enzymes from control, phenobarbital (PB) and 3-methylcholanthrene (MC) treated rats. 2. SKF 525A and cimetidine inhibited more potently hepatic AHH than the placental enzyme. 7,8-Benzoflavone inhibited more efficiently placental AHH than the hepatic enzyme, whereas ERDE was inhibited at the same level in both tissues. Quinine, quinidine, SKF 525A and metyrapone inhibited ERDE almost to the same extent in both tissues, but the variability was larger with the liver enzyme. Aminoglutethimide, debrisoquine or tetrahydrofuran did not inhibit AHH or ERDE significantly in either tissue. 3. When compared with inhibition profiles obtained with rat liver microsomes, the human hepatic and placental ERDE resembled most that of MC-treated rat liver enzyme. Inhibition profile of placental AHH activity was also similar, but the inhibition characteristics of hepatic AHH activity resembled more closely control or PB-induced rat liver. It also seems that isozymes for alcohol induction or debrisoquine hydroxylation do not contribute significantly to hepatic or placental AHH or ERDE. 4. The inhibitor panel selected on the basis of known pretreatment and isozyme specificity might be useful in the characterization of enzymes and metabolic biotransformations participating in the metabolism of new substrates.
Pasanen
M
M
Department of Pharmacology, University of Oulu, Finland.
Taskinen
T
T
Sotaniemi
E A
EA
Kairaluoma
M
M
Pelkonen
O
O
D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003647:Debrisoquin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005663:Furans; D007527:Isoenzymes; D000616:Aminoglutethimide; C018674:tetrahydrofuran; C011512:alpha-naphthoflavone; D002927:Cimetidine; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D003647:Debrisoquin; D008797:Metyrapone