Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans.

To evaluate a stereoselective interaction for amiodarone and racemic warfarin, we performed a prospective study with its separated enantiomorphs. Single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects, with and without oral amiodarone, 400 mg daily, for the hypoprothrombinemic duration.

Inactivation of multiple hepatic cytochrome P-450 isozymes in rats by allylisopropylacetamide: mechanistic implications.

In vivo administration of the porphyrogenic agent allylisopropylacetamide (AIA) to phenobarbital-pretreated rats results in marked loss of hepatic cytochrome P-450 content. Using isozyme-selective functional markers, we now show that such loss reflects inactivation of several phenobarbital-inducible and constitutive isozymes. Some of the isozymes (P-450a,b,h and PB-1) are largely reparable by reconstitution with exogenous hemin, indicating that after AIA-mediated loss of their prosthetic heme, their apoprotein moieties are essentially intact and functionally reconstitutable with hemin.

Cytochrome P-450--catalyzed formation of delta 4-VPA, a toxic metabolite of valproic acid.

Liver damage induced by the antiepileptic drug valproic acid (VPA) is believed to be mediated by an unsaturated metabolite of the drug, delta 4-VPA. In studies of the biological origin of this hepatotoxic compound, it was found that liver microsomes from phenobarbital-treated rats catalyzed the desaturation of VPA to delta 4-VPA. Indirect evidence suggested that cytochrome P-450 was the responsible enzyme, a conclusion that was verified by studies with a purified and reconstituted form of the hemoprotein, which catalyzed the oxidation of VPA to 4- and 5-hydroxyvalproic acid and to delta 4-VPA.

Major differences between lung, skin and liver in the microsomal metabolism of homologous series of resorufin and coumarin ethers.

Phenoxazone and a homologous series of its ethers (methoxy to octoxy plus benzyloxy), and coumarin and a series of its ethers (methoxy to propoxy), were metabolized by liver, lung and skin microsomes of normal adult female BALB/c mice. For each series of substrates, and with each tissue, clear structure-activity relationships were seen, relating metabolic activity to the length of the ether side-chain. With the coumarin series of substrates the structure-activity relationships were almost identical in the three tissues, with liver more active than lung and lung more active than skin.

Valproate hydroxylation by human fetal tissues and embryotoxicity of metabolites.

The oxidative biotransformation of sodium valproate was studied in liver, lung, brain, and adrenal homogenates from human conceptuses with gestational ages ranging from 50 to 77 days. Analyses of metabolites by GC/MS indicated the formation of 3-hydroxy-, 4-hydroxy-, and 5-hydroxyvalproic acid, with hydroxylation occurring preferentially at the 4- position. The adrenal homogenate was consistently the most active fetal tissue studied, with rates of hydroxylation similar to those in rat and macaque liver homogenates.

Cytosolic activation of hematin-dependent microsomal monooxygenase activity in the lung.

Additions of micromolar concentrations of hematin to washed rat pulmonary microsomal preparations resulted in marked (5-7-fold) increases in the NADPH-dependent generation of phenolic metabolites of benzo[a]pyrene (BaP). 9-Hydroxy-BaP was identified as the major reaction product. Additions of pulmonary cytosolic fractions to microsomes produced no measurable effect but cytosol and hematin added together elicited 25-30-fold increases in total phenolic products.

Substrate specificity of the mouse skin mixed-function oxidase system.

The metabolism of nine model substrates for the mixed-function oxidase system was studied in skin and liver microsomes from Balb/C mice. Rates of skin metabolism per mg microsomal protein ranged from 0.5-15% of liver rates depending on the substrate.

Stereoselective and regioselective hydroxylation of warfarin and selective O-dealkylation of phenoxazone ethers in human placenta.

The oxidative metabolism of warfarin and a series of phenoxazone ethers was studied in two groups of human placentas which exhibited high or low levels of aryl hydrocarbon hydroxylase (AHH). Warfarin metabolism was stereoselective (mean R/S = 2.48) for the R-enantiomer and regioselective for the 6- and 8- positions in the high AHH group whereas warfarin metabolism in the low AHH group displayed no significant overall stereoselectivity (mean R/S = 1.