ABSTRACT
A series of N-substituted heteroaromatic compounds structurally related to clotrimazole was synthesized, and the effects of these compounds on ethosuximide clearance in rats were determined as a measure of their abilities to induce cytochrome P4503A (CYP3A) activity. Ethosuximide clearance and in vitro erythromycin N-demethylase activity were shown to correlate. In this series, imidazole or other related heteroaromatic "head groups" were linked to triphenylmethane or other phenylmethane derivatives. Within the series, it was found that 1-triphenylmethane-substituted imidazoles elicited the greatest increase in CYP3A activity, and that among the triphenylmethyl-substituted imidazoles, the highest activities were achieved by the substitution of F- or Cl- in either the meta or para position of one of the phenyl rings. Diphenylmethyl-substituted pyridine was effectively devoid of activity. Compounds eliciting the largest increase in CYP3A activity (viz. 1-[(3-fluorophenyl)diphenylmethyl]imidazole, 1-[(4-fluorophenyl)diphenylmethyl]imidazole, and 1-[tri-(4-fluorophenyl)methyl]imidazole) produced little or no increase in ethoxyresorufin O-dealkylase (EROD) activity (i.e. CYP1A), whereas benzylimidazole, which elicited only a small increase in CYP3A activity, produced an almost 9-fold increase in CYP1A activity. For a series of eleven compounds exhibiting a wide range of influence on CYP3A activity, a positive correlation was found between ethosuximide clearance and hepatic CYP3A mRNA levels.
Subject(s)
Aryl Hydrocarbon Hydroxylases , Azoles/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Oxidoreductases, N-Demethylating/metabolism , Pyridines/pharmacology , Animals , Azoles/chemical synthesis , Azoles/chemistry , Clotrimazole/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/biosynthesis , Enzyme Induction , Ethosuximide/pharmacokinetics , Liver/drug effects , Liver/enzymology , Male , Oxidoreductases, N-Demethylating/biosynthesis , Pyridines/chemical synthesis , Pyridines/chemistry , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A boar with testicular hypoplasia had 39 chromosomes. Giemsa banded preparations permitted unambiguous identification of an XXY sex chromosome constitution. Spermatogenic tissue was absent as in X chromatin-positive Klinefelter syndrome of man.
