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Studies on modifiers of microsomal drug oxidation.

Authors
Leibman-KC
Source
Chem-Biol Interact 1971 Aug; 3(4):289-290
NIOSHTIC No.
00186811
Abstract
Studies on modifiers of hepatic microsomal drug metabolism were summarized. The effect of metyrapone (54364), a potent adrenal steroid hydroxylase inhibitor, on hepatic microsomal acetanilide- hydroxylase (AcOHase) was described. Metyrapone exerted a biphasic effect, moderate doses being stimulatory and high doses being inhibitory. Similar biphasic effects on AcOHase or aniline- hydroxylase (AnOHase) have been observed with acetone (67641), acetophenone (98862), alpha,alpha'-dipyridyl (366187) (AADP), and o- phenanthroline (66717) (phenanthroline) which all have structural features in common with metyrapone. Other compounds that affect AcOHase, AnOHase, or aminopyrine-demethylase (APDN) such as clofibrate (637070), 2-(p-aminophenyl)-2-phenylethylamine (6578310) (SKF-12185), 1-(2-isopropylphenyl)imidazole (25364403) (IPI), and 1- (2-cyanophenyl)imidazole (25373493) (CPI) were described. Whereas SKF-12185 and clofibrate readily inhibit adrenal steroid hydroxylation, they are rather weak inhibitors of hepatic microsomal AcOHase, AnOHase, or APDN. The concentrations for 50 percent inhibition (IC50) of AcOHase, AnOHase, and APDN are on the order of 1 millimolar. IPI and CPI are very potent inhibitors, the respective IC50s for APDN being 0.5 and 10 micromolar. IPI has been found to prolong hexobarbital sleeping time in rats to about five times the control value and to cause 33 percent mortality. The spectrophotometric properties of metyrapone were discussed. Metyrapone produces a type-II difference spectrum when added to liver microsomes. Acetophenone, AADP, and phenanthroline do not produce a characteristic difference spectrum when added to either oxidized or reduced liver microsomes. The author concludes that the ability of metyrapone to produce a type-II difference spectrum is not related to its effect on AcOHase.
Keywords
NIOSH-Publication; NIOSH-Grant; Liver-microsomal-metabolism; In-vivo-studies; Absorption-spectrophotometry; Laboratory-animals; In-vitro-studies; Drugs; Oxidative-processes; Grants-other
Contact
Pharmacology and Therapeutics Univ of Florida Coll of Med Dept of Pharma & Therapeutics Gainesville, Fla 32601
CODEN
CBINA8
CAS No.
54-36-4; 67-64-1; 98-86-2; 366-18-7; 66-71-7; 637-07-0; 6578-31-0; 25364-40-3; 25373-49-3
Publication Date
19710801
Document Type
Journal Article
Funding Amount
460733.00
Funding Type
Grant
Fiscal Year
1971
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-00316
Issue of Publication
4
ISSN
0009-2797
Priority Area
Other Occupational Concerns; Grants-other
Source Name
Chemico-Biological Interactions
State
FL
Performing Organization
University of Florida Gainesville, Gainesville, Florida
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