Abstract
Xenobiotics that induce the cytochromes P450 also produce changes in rat hepatic sulfotransferase (SULT) gene expression. In the present study, male Sprague-Dawley rats were treated for 3 consecutive days with doses of phenobarbital (PB) that induce cytochrome P450 2B1/2 expression. The effects of PB treatment on hepatic aryl SULT (SULT1) and hydroxysteroid SULT (SULT2) mRNA and immunoreactive protein levels and on mRNA expression of individual SULT1 and SULT2 enzyme isoforms were characterized. PB suppressed SULT1A1 mRNA levels, increased the expression of the SULT-Dopa/tyrosine isoform, and did not produce significant changes in SULT1C1 and SULT1E2 mRNA expression. In rats injected with the highest test dose of PB (100 mg/kg), hepatic SULT1A1 mRNA levels were decreased to ∼42% of control levels and SULT-Dopa/tyrosine mRNA levels were increased to ∼417% of vehicle-treated control levels. Like the SULT1 subfamily, individual members of the SULT2 gene subfamily were differentially affected by PB treatment. PB (35, 80, and 100 mg/kg) suppressed SULT20/21 mRNA expression to ∼61, ∼30, and ∼41% of vehicle-treated control levels, respectively. In contrast, SULT60 mRNA levels were increased to ∼162% of control levels and SULT40/41 mRNA levels were increased to ∼416% of vehicle-treated control levels in rats treated with 100 mg/kg PB. These studies support a complex role for PB-mediated effects on the SULT multigene family in rat liver. Because individual SULT1 and SULT2 enzyme isoforms are known to metabolize a variety of potentially toxic substrates, varied responses to PB among members of the SULT multigene family might have important implications for xenobiotic hepatotoxicity.
Footnotes
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Send reprint requests to: Melissa Runge-Morris, M.D., Institute of Chemical Toxicology, Wayne State University, 2727 Second Avenue, Detroit, MI 48201.
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This work was supported by National Institutes of Health Grants ES05823 (M.R.-M.) and HL50710 (T.A.K.).
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↵2 Proposed nomenclature for the SULT gene family is from the Workshop on Sulfotransferase Enzyme Nomenclature, Annual Meeting of the International Society for the Study of Xenobiotics (Seattle, WA, August 28, 1995).
- Abbreviations used are::
- SULT1
- aryl sulfotransferase
- SULT
- sulfotransferase
- ANOVA
- analysis of variance
- CYP or P450
- cytochrome P450
- PB
- phenobarbital
- SDS
- sodium dodecyl sulfate
- SULT2
- hydroxysteroid sulfotransferase
- ECL
- enhanced chemiluminescence
- EST
- estrogen sulfotransferase
- RT-PCR
- reverse transcription-polymerase chain reaction
- SSC
- standard saline citrate
- Received January 22, 1998.
- Accepted April 1, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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