Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man
The common genetic deficiency of drug oxidation known as debrisoquine/sparteine-type polymorphism was investigated with bufuralol as prototype substrate. In human liver microsomes the 1'-hydroxylation of bufuralol is catalyzed by two functionally distinct P-450 isozymes, the high-affinity/highly stereoselective P450bufI and the low-affinity/nonstereoselective P450bufII. The authors demonstrate that P450bufI is unique in hydroxylating bufuralol in a cumene hydroperoxide (CuOOH) mediated reaction whereas P450bufII is active only in the classical NADPH- and O/sub 2/-supported monooxygenation. In microsomes of liver biopsies of in vivo phenotyped poor metabolizers of debrisoquine or sparteine, the CuOOH-mediated activity was drastically reduced. Rabbit antibodies against a rat P-450 isozyme with high bufuralol 1'-hydroxylase activity (P450db1) precipitated exclusively P450bufI-type activity from solubilized microsomes. Western blotting of microsomes with these antibodies revealed a close correlation between the immunoreactive protein and CuOOH-mediated (+)-bufuralol 1'-hydroxylation. No immunoreactive protein was detected in liver microsomes of in vivo phenotyped poor metabolizers. These data provide evidence for a specific deficiency of P450bufI and are consistent with the complete or almost complete absence of this protein in the liver of poor metabolizers.
- Research Organization:
- Univ. of Basel (Switzerland)
- OSTI ID:
- 7002043
- Journal Information:
- Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 27:15; ISSN BICHA
- Country of Publication:
- United States
- Language:
- English
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550601 -- Medicine-- Unsealed Radionuclides in Diagnostics
59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ANIMALS
ANTIBODIES
AUTORADIOGRAPHY
BIOCHEMISTRY
BODY
CELL CONSTITUENTS
CHEMICAL REACTIONS
CHEMISTRY
CYTOCHROME OXIDASE
CYTOCHROMES
DIGESTIVE SYSTEM
DISEASES
DRUGS
ELECTROPHORESIS
ENZYMES
GLANDS
HAEM DEHYDROGENASES
HEREDITARY DISEASES
HYDROXYLATION
ISOENZYMES
LIVER
MAMMALS
METABOLISM
MICROSOMES
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
OXIDATION
OXIDOREDUCTASES
PATIENTS
PIGMENTS
PROTEINS
RABBITS
VERTEBRATES