Bifunctional modulating effects of an indigo dimer (bisindigotin) to CYP1A1 induction in H4IIE cells

K. P. LAI, N. K. MAK, X. WEI, R. N. S. WONG, Ming Hung WONG, Chris K. C. WONG

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In this study, we measured and characterized the bifunctional effects of a newly identified natural compound-bisindigotin (SLY-1), isolated from leaf extracts of Isatis indigotica, to CYP1A1/EROD activities in H4IIE cells. The compound, SLY-1 (1 μM) elicited a transitory and significant induction of CYP1A1 RNA/protein levels and EROD activities in the cells. Maximum levels of CYP1A1 expression and EROD induction were attained at 8 and 12 h of post-treatment, respectively. Thereafter the induction decreased significantly. Similar profile of CYP1A2 and CYP1B1 mRNA induction was observed. In contrast TCDD elicited CYP1A1/EROD induction was persistent. The transitory effect by SLY-1 is most likely due to the clearance of SLY-1 by cellular metabolism. Taken together the observation indicated that SLY-1 is an Ah receptor agonist for CYP1A1/CYP1A2/CYP1B1/EROD induction. Interestingly in the TCDD/SLY-1 cotreatment study, although synergistic effects on CYP1A1 expression and EROD induction were observed at 4-8 h, significant inhibitory effects to TCDD induced CYP1A1 protein and EROD activity were detected at 12-24 h of post-treatment. Because there was no significant reduction of CYP1A1, CYP1A2 or CYP1B1 transcript levels between TCDD- and TCDD/SLY-1 treated cells, the data pointed to the translational and/or post-translational inhibitory effect. The cellular signal transduction system may be modulated following exposure to SLY-1. To investigate the possible mechanisms involved, various specific kinase inhibitors or activators (chelerythrin, PD98059, U0126, ZM336372, SB202190, PKA inhibitor PKI (6-22) amide, and dbcAMP) were used for the assessment. Chelerythrine, PD98059 or dbcAMP treatment in TCDD induced cells showed significant inhibitory effects on CYP1A1 mRNA/protein expressions and EROD activities. U0126 had no observable EROD inhibitory effect. ZM336372 or SB202190 showed inhibition only at EROD activities. The results indicated that the SLY-1 inhibitory effect was possibly not mediated by the cAMP/PKA, PKC or MEK pathways. Nevertheless our results indicate that SLY-1 is not only an inducer of the CYP1A1 system, but also a potent inhibitor of CYP1A1 enzyme. Copyright © 2006 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)188-196
JournalToxicology
Volume226
Issue number2-3
DOIs
Publication statusPublished - 21 Sep 2006

Fingerprint

Indigo Carmine
Cytochrome P-450 CYP1A1
Dimers
Cytochrome P-450 CYP1A2
Isatis

Citation

Lai, K. P., Mak, N. K., Wei, X., Wong, R. N. S., Wong, M. H., & Wong, C. K. C. (2006). Bifunctional modulating effects of an indigo dimer (bisindigotin) to CYP1A1 induction in H4IIE cells. Toxicology, 226(2-3), 188-196. doi: 10.1016/j.tox.2006.06.016

Keywords

  • CTP1A2
  • CTP1B1
  • EROD