Inhibition of hepatic microsomal cytochrome P-450 dependent monooxygenation activity by the antioxidant 3-tert-butyl-4-hydroxyanisole
| Autor: | Rodrigues Ad, Nosarzewski Ma, Pierce Wm, David Fernandez, Russell A. Prough |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Male
Hemeprotein Cytochrome Stereochemistry 25-Hydroxyvitamin D3 1-alpha-hydroxylase Butylated Hydroxyanisole Toxicology Antioxidants Hydroxylation chemistry.chemical_compound Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A2 Cytochrome c oxidase Animals Cytochrome P-450 Enzyme Inhibitors Ferrous Compounds biology CYP1A2 Cytochrome P450 Cytochrome P450 reductase General Medicine Glutathione Kinetics Biochemistry chemistry biology.protein Microsomes Liver Oxygenases Rabbits Oxidoreductases Oxidation-Reduction |
| Zdroj: | Chemical research in toxicology. 4(3) |
| ISSN: | 0893-228X |
| Popis: | The efficacy of 3-tert-butyl-4-hydroxyanisole (BHA) as a chemopreventive agent against chemically induced cancer or toxicity may involve the direct modulation of cytochrome P-450 dependent monooxygenase function. This hypothesis was investigated by using purified rabbit cytochrome P-450IA2 and P-450IIB4 in a reconstitution system with purified NADPH:cytochrome P-450 oxidoreductase and L-alpha-dilauroylphosphatidylcholine. BHA caused a concentration-dependent decrease in cytochrome P-450IIB4 dependent 7-ethoxycoumarin O-deethylation, cyclohexane hydroxylation, and benzphetamine N-demethylation activities (IC50; 28, 75, and 290 microM, respectively) and in cytochrome P-450IA2 dependent 7-ethoxyresorufin O-deethylation and acetanilide para hydroxylation activities (IC50 approximately 225 microM). The inhibition of monooxygenation activity was accompanied by redox cycling due to the tert-butylquinone produced during BHA metabolism, as measured by increased NADPH and oxygen consumption or hydrogen peroxide and superoxide anion production. Glutathione was shown to reverse this redox cycling phenomenon but did not reverse the BHA-dependent inhibition of monooxygenation activity. Using standard steady-state kinetic analyses, BHA was shown to be a mixed-type competitive inhibitor of benzphetamine metabolism by cytochrome P-450IIB4, suggesting that BHA does not simply compete as an alternate substrate for the hemoprotein but must also bind to another catalytically functional form of cytochrome P-450. BHA was shown to bind as a ligand to both purified and microsomal cytochrome P-450IA2, resulting in a low to high (type I) spin-state perturbation.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
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