Document Detail


Effect of arsenite on induction of CYP1A, CYP2B, and CYP3A in primary cultures of rat hepatocytes.
MedLine Citation:
PMID:  10329507     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In earlier studies, sodium arsenite treatment was shown to decrease induction of enzymatic activities associated with hepatic CYPs in rats. Here we investigated the effect of sodium arsenite on induction of CYP2B, CYP1A, and CYP3A in primary cultures of rat hepatocytes. Arsenite decreased the induction of all three families of CYP, as measured enzymatically and immunochemically. These decreases in CYPs occurred at concentrations of arsenite (2.5-10 microM) at which no toxicity was observed; however, toxicity was observed at 25 microM arsenite. With 3-methylcholanthrene as inducer, 5 microM arsenite caused a 55% decrease in CYP1A1 immunoreactive protein and enzyme activity, but only a 25% decrease in CYP1A1 mRNA. With phenobarbital (PB) as the inducer, 2.5 microM arsenite decreased CYP2B enzyme activity and immunoreactive protein 50%, with only a 25% decrease in CYP2B1 mRNA. 5 microM Arsenite decreased CYP2B enzyme activity and immunoreactive protein 80%, but decreased CYP2B1 mRNA only 50%, while CYP3A protein was decreased greater than 75% with no decrease in CYP3A23 mRNA. With dexamethasone (DEX) as inducer, 5 microM sodium arsenite caused a 50% decrease in immunoreactive CYP3A and a 30% decrease in CYP3A23 mRNA. Although arsenite-mediated increases in heme oxygenase (HO) inversely correlated with decreases in CYP2B or CYP1A activity, inclusion of heme in cultures treated with inducers of CYP1A or CYP2B did not prevent the arsenite-mediated decreases in these CYPs. Even though added heme induced HO to similar levels with and without arsenite, decreases in CYPs were only observed in the presence of arsenite. These results suggest that, in rat hepatocytes, elevated levels of HO alone are not responsible for arsenite-mediated decreases in CYP.
Authors:
J M Jacobs; C E Nichols; A S Andrew; D E Marek; S G Wood; P R Sinclair; S A Wrighton; V E Kostrubsky; J F Sinclair
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  157     ISSN:  0041-008X     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-06-17     Completed Date:  1999-06-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  51-9     Citation Subset:  IM    
Copyright Information:
Copyright 1999 Academic Press.
Affiliation:
Veterans Administration Medical Center, White River Junction, Vermont, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arsenites / toxicity*
Aryl Hydrocarbon Hydroxylases*
Cells, Cultured
Cytochrome P-450 CYP1A1 / biosynthesis*,  genetics
Cytochrome P-450 CYP2B1 / biosynthesis*,  genetics
Cytochrome P-450 Enzyme System / biosynthesis*,  genetics
Enzyme Induction / drug effects
Heme Oxygenase (Decyclizing) / metabolism
Liver / cytology,  drug effects*,  enzymology
Male
RNA, Messenger / analysis
Rats
Rats, Inbred F344
Grant Support
ID/Acronym/Agency:
ES 07373/ES/NIEHS NIH HHS; ES06203/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Arsenites; 0/RNA, Messenger; 15502-74-6/arsenite; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP3A23 protein, rat; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/Cytochrome P-450 CYP2B1; EC 1.14.99.3/Heme Oxygenase (Decyclizing)

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