Abstract
1. Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by 12 recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes have been investigated. 2. Arachidonic acid (50 microM) significantly inhibited CYP1A1- and 1A2-dependent 7-ethoxycoumarin O-deethylations, CYP2C8-dependent taxol 6alpha-hydroxylation and CYP2C19-dependent R-warfarin 7-hydroxylation. This chemical also inhibited slightly the xenobiotic oxidations catalysed by CYP1B1, 2B6, 2C9, 2D6, 2E1 and 3A4 in recombinant enzyme systems. 3. Retinol, retinoic acid and cholecalciferol were strong inhibitors for xenobiotic oxidations catalysed by recombinant CYP1A1, 2C8 and 2C19. 4. Dixon plots of inhibitions of CYP1A1-, 1A2-, 2C8- and 2C19-dependent xenobiotic oxidations by arachidonic acid, of CYP1A1-, 2B6- and 2C19-dependent activities by retinol, and of CYP1A1- and 2C19-dependent activities by cholecalciferol indicated that these chemicals inhibit P450 activities mainly through a competitive mechanism. 5. In human liver microsomes, arachidonic acid inhibited CYP1A2-dependent theophylline hydroxylation, CYP2C8-dependent taxol 6alpha-hydroxylation and CYP2C19-dependent omeprazole 5-hydroxylation. Taxol 6alpha-hydroxylation was also inhibited by retinol and retinoic acid, and omeprazole 5-hydroxylation was inhibited by retinol in human liver microsomes. 6. These results suggest that xenobiotic oxidations by P450 enzymes are affected by endobiotic chemicals and that the endobiotic-xenobiotic interactions as well as drug-drug interactions may be of great importance when understanding the basis for pharmacological and toxicological actions of a number of xenobiotic chemicals.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Arachidonic Acid / metabolism
-
Arachidonic Acid / pharmacology*
-
Aryl Hydrocarbon Hydroxylases*
-
Cholecalciferol / metabolism
-
Cholecalciferol / pharmacology*
-
Coumarins / metabolism
-
Cytochrome P-450 CYP1A1 / drug effects
-
Cytochrome P-450 CYP1A1 / metabolism
-
Cytochrome P-450 CYP1A2 / drug effects
-
Cytochrome P-450 CYP1A2 / metabolism
-
Cytochrome P-450 CYP1B1
-
Cytochrome P-450 CYP2A6
-
Cytochrome P-450 CYP2B6
-
Cytochrome P-450 CYP2C19
-
Cytochrome P-450 CYP2C8
-
Cytochrome P-450 CYP2E1 / metabolism
-
Cytochrome P-450 CYP3A
-
Cytochrome P-450 CYP4A
-
Cytochrome P-450 Enzyme System / drug effects
-
Cytochrome P-450 Enzyme System / metabolism*
-
Ethanolamines / metabolism
-
Humans
-
Isoenzymes / metabolism
-
Lauric Acids / metabolism
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / metabolism
-
Mixed Function Oxygenases / metabolism
-
Nifedipine / metabolism
-
Omeprazole / metabolism
-
Oxidation-Reduction
-
Oxidoreductases, N-Demethylating / metabolism
-
Paclitaxel / metabolism
-
Prostaglandins / metabolism
-
Prostaglandins / pharmacology*
-
Recombinant Proteins / drug effects
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Steroid 16-alpha-Hydroxylase*
-
Steroid Hydroxylases / metabolism
-
Theophylline / metabolism
-
Tretinoin / metabolism
-
Tretinoin / pharmacology*
-
Warfarin / metabolism
-
Xenobiotics / metabolism*
Substances
-
Coumarins
-
Ethanolamines
-
Isoenzymes
-
Lauric Acids
-
Prostaglandins
-
Recombinant Proteins
-
Xenobiotics
-
lauric acid
-
Cholecalciferol
-
Arachidonic Acid
-
7-ethoxycoumarin
-
Tretinoin
-
Warfarin
-
bufuralol
-
Cytochrome P-450 Enzyme System
-
coumarin
-
Theophylline
-
Mixed Function Oxygenases
-
Steroid Hydroxylases
-
Cytochrome P-450 CYP2E1
-
Aryl Hydrocarbon Hydroxylases
-
CYP1A2 protein, human
-
CYP1B1 protein, human
-
CYP2B6 protein, human
-
CYP2C19 protein, human
-
CYP2C8 protein, human
-
CYP3A protein, human
-
Cytochrome P-450 CYP1A1
-
Cytochrome P-450 CYP1A2
-
Cytochrome P-450 CYP1B1
-
Cytochrome P-450 CYP2A6
-
Cytochrome P-450 CYP2B6
-
Cytochrome P-450 CYP2C19
-
Cytochrome P-450 CYP2C8
-
Cytochrome P-450 CYP3A
-
Steroid 16-alpha-Hydroxylase
-
Cytochrome P-450 CYP4A
-
Oxidoreductases, N-Demethylating
-
Nifedipine
-
Omeprazole
-
Paclitaxel