In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver

Vladimir O. Pustylnyak, Lyudmila Yu Zakharova, Olga N. Mikhailova, Robert H. Rice, Lyudmila F. Gulyaeva, Vyacheslav V. Lyakhovich

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Effects of inhibiting protein kinases and phosphatases on induction of CYP2B by triphenyldioxane (TPD) and phenobarbital (PB) were investigated. Male Wistar rats were treated with test inhibitors before TPD or PB administration. Inhibitors of phosphatidylinositol-3-kinase (Wortmannin) and protein kinase C (bisindolylmaleimide I) did not have appreciable effects on TPD- or PB-induced pentoxyresorufin O-dealkylase (PROD) activity specific for CYP2B, although bisindolylmaleimide I did give substantial induction alone. W-7, an inhibitor of Ca 2+/calmodulin-dependent kinase II, produced a 6-fold increase in the TPD-induced PROD activity and did not lead to a significant increase in basal PROD activity. Treatment of rats with okadaic acid (OA), an inhibitor of protein phosphatases PP1 and PP2A, caused considerable decreases in PROD activity during the induction by TPD and PB (8- and 2.5-fold, respectively). Results of multiplex RT-PCR showed that the increase in enzymatic activity from W7 and OA treatment reflected at least in part increased mRNA levels. CYP2B mRNA level in the liver of rats treated with W-7 and TPD was 1.5 times higher than in the liver of TPD-treated rats. This effect was not observed for PB-induction. OA treatment caused a decrease of the CYP2B mRNA levels of 44% and 33% respectively, for TPD- and PB-induction. Thus, our results are consistent with the hypothesis that phosphorylation/dephosphorylation signaling pathways are involved in regulation of CYP2B induction in rat liver.

Original languageEnglish (US)
Pages (from-to)315-322
Number of pages8
JournalToxicology
Volume207
Issue number2
DOIs
StatePublished - Feb 14 2005

Fingerprint

Phosphoprotein Phosphatases
Protein Kinase Inhibitors
Phenobarbital
Cytochrome P-450 CYP2B1
Liver
Protein Kinases
Rats
Okadaic Acid
Messenger RNA
Phosphatidylinositol 3-Kinase
Calcium-Calmodulin-Dependent Protein Kinases
Phosphorylation
Multiplex Polymerase Chain Reaction
Calmodulin
Protein Kinase C
Wistar Rats
Phosphotransferases
W 7

Keywords

  • Cytochrome P4502B
  • Induction
  • Inhibitors of protein kinases and phosphatases
  • Phenobarbital
  • Rat liver
  • Triphenyldioxane

ASJC Scopus subject areas

  • Toxicology

Cite this

Pustylnyak, V. O., Zakharova, L. Y., Mikhailova, O. N., Rice, R. H., Gulyaeva, L. F., & Lyakhovich, V. V. (2005). In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver. Toxicology, 207(2), 315-322. https://doi.org/10.1016/j.tox.2004.10.003

In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver. / Pustylnyak, Vladimir O.; Zakharova, Lyudmila Yu; Mikhailova, Olga N.; Rice, Robert H.; Gulyaeva, Lyudmila F.; Lyakhovich, Vyacheslav V.

In: Toxicology, Vol. 207, No. 2, 14.02.2005, p. 315-322.

Research output: Contribution to journalArticle

Pustylnyak, VO, Zakharova, LY, Mikhailova, ON, Rice, RH, Gulyaeva, LF & Lyakhovich, VV 2005, 'In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver', Toxicology, vol. 207, no. 2, pp. 315-322. https://doi.org/10.1016/j.tox.2004.10.003
Pustylnyak VO, Zakharova LY, Mikhailova ON, Rice RH, Gulyaeva LF, Lyakhovich VV. In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver. Toxicology. 2005 Feb 14;207(2):315-322. https://doi.org/10.1016/j.tox.2004.10.003
Pustylnyak, Vladimir O. ; Zakharova, Lyudmila Yu ; Mikhailova, Olga N. ; Rice, Robert H. ; Gulyaeva, Lyudmila F. ; Lyakhovich, Vyacheslav V. / In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver. In: Toxicology. 2005 ; Vol. 207, No. 2. pp. 315-322.
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abstract = "Effects of inhibiting protein kinases and phosphatases on induction of CYP2B by triphenyldioxane (TPD) and phenobarbital (PB) were investigated. Male Wistar rats were treated with test inhibitors before TPD or PB administration. Inhibitors of phosphatidylinositol-3-kinase (Wortmannin) and protein kinase C (bisindolylmaleimide I) did not have appreciable effects on TPD- or PB-induced pentoxyresorufin O-dealkylase (PROD) activity specific for CYP2B, although bisindolylmaleimide I did give substantial induction alone. W-7, an inhibitor of Ca 2+/calmodulin-dependent kinase II, produced a 6-fold increase in the TPD-induced PROD activity and did not lead to a significant increase in basal PROD activity. Treatment of rats with okadaic acid (OA), an inhibitor of protein phosphatases PP1 and PP2A, caused considerable decreases in PROD activity during the induction by TPD and PB (8- and 2.5-fold, respectively). Results of multiplex RT-PCR showed that the increase in enzymatic activity from W7 and OA treatment reflected at least in part increased mRNA levels. CYP2B mRNA level in the liver of rats treated with W-7 and TPD was 1.5 times higher than in the liver of TPD-treated rats. This effect was not observed for PB-induction. OA treatment caused a decrease of the CYP2B mRNA levels of 44{\%} and 33{\%} respectively, for TPD- and PB-induction. Thus, our results are consistent with the hypothesis that phosphorylation/dephosphorylation signaling pathways are involved in regulation of CYP2B induction in rat liver.",
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AU - Rice, Robert H.

AU - Gulyaeva, Lyudmila F.

AU - Lyakhovich, Vyacheslav V.

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