Selective inactivation of four rat liver microsomal androstenedione hydroxylases by chloramphenicol analogs
KeywordsChloramphenicol -- Toxicology.
Isoenzymes -- Effect of drugs on.
Antibiotics -- Toxicology.
AdvisorHalpert, James R.
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PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe steroid androstenedione has been shown to be a valuable tool for the study of selective inactivation of rat liver cytochrome P-450 isozymes. The validity of this method was investigated using microsomes, purified cytochromes P-450, cytochrome P-450 antibodies, and the mechanism-based inactivator chloramphenicol. Enzyme inactivation and antibody inhibition studies show that microsomes from phenobarbital- and non-phenobarbital-treated rats are needed to accurately monitor the inactivation of the major phenobarbital-inducible P-450 isozyme (PB-B) and of the major constitutive androstenedione 16-alpha hydroxylase (UT-A). Enzyme inactivation studies showed that the antibiotic chloramphenicol caused different rates of NADPH-dependent enzyme inactivation among four androstenedione hydroxylases (16-beta > 6-beta > 16-alpha > 7-alpha). The results with twelve chloramphenicol analogs show that their selectivity as cytochrome P-450 inactivators is dependent upon at least three structural features: (1) the number of halogen atoms, (2) the presence of a para-nitro group on the phenyl ring, and (3) substitutions on the ethyl side chain.
Degree ProgramGraduate College
Pharmacology and Toxicology