Pregnenolone-16a -carbonitrile

Figure 13.2 Schematic representation of the creation of hPXR humanized mice. The humanization was achieved in the liver only when the liver-specific albumin promoter was used to direct the transgene expression, or in both the liver and the intestine when the fatty acid binding protein promoter was used. PCN, pregnenolone-16a-carbonitrile RIF, rifampicin. + and mean induction and lack of induction, respectively.

Lu, A.Y.H., Somogyi, A., West, S., Kuntzman, R., and Conney, A.H. Pregnenolone- 16a-carbonitrile A new type of inducer of drug-metabolizing enzymes. Arch. Biochem. Biophys. 

Rifampicin and pregnenolone-16a-carbonitrile (PCN) induce members of the CYP3A family and represent a third type of inducer, in that the substrate specificity of the microsomes from treated animals differs from that of the microsomes from either phenobarbital-treated or TCDD-treated animals. Inducing substrates of this class include endogenous and synthetic glucocorticoids (e.g., dexamethasone), pregnane... 

P450 IIIA4 Human nf Pregnenolone, 16a-carbonitrile Ethinylestradiol Nifedipine N-oxidase... 

Marek, C.J., Tucker, S.J., Konstantinou, D.K., Elrick, L.J., Haefner, D., Sigalas, C., Murray, G.I., Goodwin, B. and Wright, M.C. (2005) Pregnenolone-16a-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptorj-dependent and PXR-independent mechanisms. The Biochemical Journal, 387, 601—608. 

Pb phenobarbital PCN pregnenolone-16a-carbonitrile 3MC 3-methylcholanthrene Aro arochlor 1254. Data from Powis et al. (1977) In Microsomes and Drug Oxidations, edited by V.Ullrich, A.Roots, A.Hildebrandt, R.W. Estabrook and A.H.Conney, p. 137 (Oxford Pergamon Press). 

Carbamazepine, dexamethasone, glutethimide, nevirapine, phenobarbital, phenytoin, pregnenolone-16a-carbonitrile, progesterone, rifabutin, rifampin, ritonavir, St. John s Wort, sulfadimidine, sulfinpyrazone, troglitazone, troleandomycin... 

DAS, diallyl sulfide TSO, fraas-stilbene oxide SJW, St. John s wort extract DEX, dexamethasone PCN, pregnenolone- 16a-carbonitrile TCPOBOP, l,4-bis-[2-(3,5-dichloropyridyloxy)]benzene PB, phenobarbital CBZ, carbamazepine CITCO, 6-(4-chlorophenyl)imidazo[2,l-b]thiazole-5-carbaldehyde 0-(3,4-dichlorobenzyl)oxime 2-AAF, 2-acetylaminofluorene. 

Guo, G. L., Staudinger, J., Ogura, K., and Klaassen, C. D. (2002) Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16a-carbonitrile is via interaction with pregnane X receptor. Mol. Pharmacol. 61, 832-839. 

Recent studies show that PXR is primarily located in the cytoplasm of untreated mouse liver [ 17]. Upon treatment with a ligand pregnenolone- 16a-carbonitrile (PCN), mouse... 

Abbreviations used DMN, dimethylnitrosamine DEN, diethylnitrosamine PB, phenobarbital 3-MC, 3-methylcholanthrene BaP, benzo[fl]pyrene )8-NF, )8-naphthoflavone PCN, pregnenolone-16a-carbonitrile AAN, aminoacetonitrile DPN, dipropylnitrosamine. 

DMN demethylase activity was repressed by pretreatment with a number of substances other than those discussed above. These include benzo[a]pyrene and numerous other PAH (72), /3-naphthoflavone (70), pregnenolone-16a-carbonitrile (70), aminoacetonitrile (70), cysteine (727, 547), nitrososarcosine (759), diethylnitrosamine (759), dibutylnitrosamine (759), dibenamine (445), and glucose (475). Other pretreatments including ethanol, isopropanol, acetone, L-tiyptophan, and casein increased DMN demethylase activity (727, 527, 450, 457, 476). The repression of DMN demethylase by substances which are often inducers of mixed-function oxidase activity is unusual although not unprecedented. These effects require further study since changes in DMN metabolism frequently result in altered toxicity or carcinogenicity. The complex pattern of induction and repression of DMN demethylase activity suggests that there are multiple forms of this enzyme. 

The effects of pregnenolone-Iba-carbonitrile and phenobarbitone, which are protective against DMN toxicity and/or carcinogenicity, on DMN metabolism in liver slices were also investigated 28, 278, 438). Pretreatment of rats with pregnenolone-16a-carbonitrile resulted in a 20% decrease in C02 production from [ C]DMN but no change in nucleic acid methylation a decrease in C02 production was also observed after phenobarbitone pretreatment. These results are in agreement with the effects of these substances on hepatic DMN demethylase I activity 10, 11). 

Poly(vinyl chloride), 32, 328 Poly(5-vinyl-8- hydroxyquinoline), 31 Poly(4-vinylpyridine), 33 Poly(vinyl pyrrolidone), 22 Potassium, 68, 69 Potassium chloride, 69 Potassium cyanocobalt(II) ferrate(Il), 36 Potassium permanganate, 28 Pregnenolone 16a-carbonitrile, 207, 208, 211, 212... 

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