3-Benzoylpyridine

Comparative induction of CYP3A and CYP2B in rat liver by 3-benzoylpyridine and metyrapone.[Pubmed:9717516]

Chem Biol Interact. 1998 Jun 5;113(3):161-73.

3-Benzoylpyridine (3BP) is a major metabolite of HGG-12, and oxime that has been synthesized as a potential antidote to the toxic effects of soman and other anticholinesterases. Structural similarities exist between 3BP, the cytochrome P450 (CYP)-inducer metyrapone (MET) and other 3-substituted pyridines that interact with CYPs. The present study evaluated the regulatory effects of 3BP on CYP expression in rat liver. Both 3BP and MET (100 mg/kg) increased total hepatic microsomal holo-CYP content significantly 24 h after administration to male rats. Pronounced increases in activities mediated by CYP2B (androstenedione 16 beta-hydroxylation and 7-pentylresorufin O-depentylation) were produced by 3BP and MET, which correlated with respective 9- and 14-fold increases in CYP2B immunoreactive protein. In addition, both agents slightly increased rates of microsomal CYP3A-dependent steroid 6 beta-hydroxylation, troleandomycin metabolite complex formation and total CYP3A immunoreactive protein. Induction of the dexamethasone-inducible CYP3A23 mRNA to 4.5- and 2.5-fold of control was detected in liver of MET- and 3BP-induced rats; CYP3A2 mRNA levels were unchanged. Analogous in vitro studies revealed that MET was a preferential inhibitor of CYP3A-mediated steroid 6 beta-hydroxylation activity, but 3BP was inactive against constitutive steroid hydroxylase CYPs. These findings indicate that the structurally related 3BP and MET elicit similar induction effects on CYPs 2B and 3A23 in rat liver after in vivo administration, but differential inhibitory effects of the chemicals on CYP activity in vitro. Recent reports have implicated a microsomal binding site in the induction of CYP3A1/3A23 in rat liver. In light of the present findings, substituted pyridines like 3BP may be useful tools in structure-activity studies to evaluate the physicochemical requirements for binding to this protein.

Dependence of the substrate specificity and kinetic mechanism of horse-liver alcohol dehydrogenase on the size of the C-3 pyridinium substituent. 3-Benzoylpyridine-adenine dinucleotide.[Pubmed:3758068]

Eur J Biochem. 1986 Sep 1;159(2):375-80.

The kinetic mechanism and the substrate specificity of liver alcohol dehydrogenase are changed when 3-Benzoylpyridine-adenine dinucleotide is used as coenzyme. Only primary alcohols are substrates of the enzyme and with ethanol the mechanism becomes rapid-equilibrium random bi-bi. According to model building experiments on a graphic display, the benzoyl group partially enters the substrate binding site, whereas the essential interactions between coenzyme and enzyme are preserved. This restraint on the substrate binding site provides a molecular explanation for the observed dependence between coenzyme and substrate chemical structures.

The metabolism of 3-benzoylpyridine.[Pubmed:6673376]

Xenobiotica. 1983 Nov;13(11):649-59.

3-Benzoylpyridine (3-BP), a decomposition product of the soman antidote, HGG-12 (3-benzoylpyridino(1)-methyl 2'-hydroxyiminomethylpyridino(1')methyl ether dichloride) was rapidly metabolized in the isolated perfused rat liver, giving 3-(alpha-hydroxybenzyl)pyridine and its corresponding glucuronide, 3-Benzoylpyridine-N-oxide, and 3-(alpha-hydroxybenzyl)pyridine-N-oxide. The latter is formed both from 3-(alpha-hydroxybenzyl)pyridine and 3-Benzoylpyridine-N-oxide. Metabolism of 3-BP studied in rats and dogs in vivo revealed significant species differences. In rat, 80% of 14C-3-BP was excreted as N-oxides and alpha-hydroxybenzyl derivatives in the urine. In dogs, 95% dose was excreted in urine mostly as the glucuronide of 3-(alpha-hydroxybenzyl)pyridine and as the quaternary pyridinium compounds, 3-benzoyl-1-methylpyridinium and 3-(alpha-hydroxybenzyl)-1-methylpyridinium. These latter were hardly detected in rat urine. In contrast to rats, the N-oxides were present only in small amounts in dog urine.