Absence of enantioselectivity in the pharmacodynamics of P450 2B induction by 5‐ethyl‐5‐phenylhydantoin in the male rat liver or in cultured rat hepatocytes

Raymond W. Nims, Jaspreet S. Sidhu, Paul E. Thomas, Donna W. Mellini, Victor C. Nelson, Curtis John Omiecinski, Ronald A. Lubet

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Abstract

To explore the enantioselectivity of ligand interaction with the putative phenobarbital receptor, the pharmacodynamics of cytochrome P450 2B (CYP2B) induction by racemic 5‐ethyl‐5‐phen‐ylhydantoin and its two enantiomers were investigated in the male F344/NCr rat and in cultured adult male rat hepatocytes. Steady‐state serum drug concentrations, measured following 14 days of administration of the compounds in the diet (0‐1320 ppm, n = 3 rats per group), were used as an approximation of intrahepatocellular drug concentration. The serum xenobiotic concentrations associated with half‐maximal hepatic CYP2B induction were 5‐10 μM, based on measurement of pentoxy‐ or benzyloxyresorufin O‐dealkylation activities, or immunoreactive CYP2B1 protein. The corresponding potency values in the hepatocyte culture experiments were 8‐12 μM, based on measurement of total cellular RNA coding for CYP2B1. In both the in vivo and the hepatocyte culture experiments, the potencies for CYP2B induction were essentially equivalent for the racemate and the individual enantiomers of 5‐ethyl‐5‐phenylhydantion. In the case of this compound, there would appear to be no enantioselectivity for CYP2B induction. This finding may be interpreted as evidence against receptor mediation in the induction of CYP2B activity, although it is also possible that a receptor is involved that does not exhibit enantioselectivity.

Original languageEnglish (US)
Pages (from-to)279-288
Number of pages10
JournalJournal of Biochemical Toxicology
Volume9
Issue number6
DOIs
StatePublished - Jan 1 1994

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Pharmacodynamics
Enantioselectivity
Liver
Cytochrome P-450 Enzyme System
Rats
Hepatocytes
Cytochrome P-450 CYP2B1
Enantiomers
Inbred F344 Rats
Xenobiotics
Nutrition
Serum
Pharmaceutical Preparations
Experiments
RNA
Diet
Ligands
Proteins

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Nims, Raymond W. ; Sidhu, Jaspreet S. ; Thomas, Paul E. ; Mellini, Donna W. ; Nelson, Victor C. ; Omiecinski, Curtis John ; Lubet, Ronald A. / Absence of enantioselectivity in the pharmacodynamics of P450 2B induction by 5‐ethyl‐5‐phenylhydantoin in the male rat liver or in cultured rat hepatocytes. In: Journal of Biochemical Toxicology. 1994 ; Vol. 9, No. 6. pp. 279-288.
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abstract = "To explore the enantioselectivity of ligand interaction with the putative phenobarbital receptor, the pharmacodynamics of cytochrome P450 2B (CYP2B) induction by racemic 5‐ethyl‐5‐phen‐ylhydantoin and its two enantiomers were investigated in the male F344/NCr rat and in cultured adult male rat hepatocytes. Steady‐state serum drug concentrations, measured following 14 days of administration of the compounds in the diet (0‐1320 ppm, n = 3 rats per group), were used as an approximation of intrahepatocellular drug concentration. The serum xenobiotic concentrations associated with half‐maximal hepatic CYP2B induction were 5‐10 μM, based on measurement of pentoxy‐ or benzyloxyresorufin O‐dealkylation activities, or immunoreactive CYP2B1 protein. The corresponding potency values in the hepatocyte culture experiments were 8‐12 μM, based on measurement of total cellular RNA coding for CYP2B1. In both the in vivo and the hepatocyte culture experiments, the potencies for CYP2B induction were essentially equivalent for the racemate and the individual enantiomers of 5‐ethyl‐5‐phenylhydantion. In the case of this compound, there would appear to be no enantioselectivity for CYP2B induction. This finding may be interpreted as evidence against receptor mediation in the induction of CYP2B activity, although it is also possible that a receptor is involved that does not exhibit enantioselectivity.",
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Absence of enantioselectivity in the pharmacodynamics of P450 2B induction by 5‐ethyl‐5‐phenylhydantoin in the male rat liver or in cultured rat hepatocytes. / Nims, Raymond W.; Sidhu, Jaspreet S.; Thomas, Paul E.; Mellini, Donna W.; Nelson, Victor C.; Omiecinski, Curtis John; Lubet, Ronald A.

In: Journal of Biochemical Toxicology, Vol. 9, No. 6, 01.01.1994, p. 279-288.

Research output: Contribution to journalArticle

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AU - Nims, Raymond W.

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