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Cytotoxicity of sanguinarine in primary rat hepatocytes is attenuated by dioxin and phenobarbital

Authors :
Eva Anzenbacherova
Jitka Ulrichová
Vilím Šimánek
Adela Zdarilova
Lucie Sperlikova
Zdenek Dvorak
Source :
Toxicology Letters. 165:282-288
Publication Year :
2006
Publisher :
Elsevier BV, 2006.

Abstract

Putative interactions between quaternary benzo[c]phenanthridine alkaloid sanguinarine (SA) and aryl hydrocarbon receptor/cytochrome P450 CYP1A (AhR/CYP1A) regulatory pathway are the subject of perpetual disputations. The role of CYP1A enzymes and AhR receptor in SA cytotoxicity was anticipated. In this paper, we tested, whether selected inducers of CYP enzymes modulate cytotoxicity of SA in primary cultures of rat hepatocytes. Cells were challenged 48h with dioxin (TCDD; 5nM), phenobarbital (PB; 500microM) or DMSO prior to the treatment with SA. SA itself displayed time- and dose-dependent cytotoxicity as revealed by lactate dehydrogenase leakage into the medium and MTT test. Pre-treatment of hepatocytes with TCDD and/or PB significantly attenuated SA cytotoxicity, the effects being more pronounced at lower concentrations of SA and shorter periods of incubation. We assumed involvement of CYP1A enzymes in diminution of SA cytotoxicity. Surprisingly, co-treatment with SA and furafylline, an inhibitor of CYP1A enzymes, further attenuated SA cytotoxicity instead of expected reversal of this effect. We conclude that TCDD- and PB-inducible genes attenuate cytotoxicity of SA in rat hepatocytes. CYP1A enzymes are not involved in this attenuation, but they rather augment SA cytotoxicity. Future research should focus on analyses of the involvement of other CYPs in SA cytotoxicity and on identification of TCDD-/PB-controlled genes responsible for observed phenomenon.

Details

ISSN :
03784274
Volume :
165
Database :
OpenAIRE
Journal :
Toxicology Letters
Accession number :
edsair.doi.dedup.....839d049ea1d0384acbe83ada8280b0b6
Full Text :
https://doi.org/10.1016/j.toxlet.2006.05.002