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Vol. 28, Issue 5, 608-616, May 2000
Environmental and Occupational Medicine Center, Department of
Pharmacology, Toxicology, and Therapeutics, University of Kansas
Medical Center, Kansas City, Kansas
The importance of the cytochrome P450 (CYP) enzyme family in
xenobiotic metabolism, as well as their differential expression and
activity in response to a wide range of environmental chemicals and
pharmaceuticals, is well documented. The objective of this study was to
evaluate the specificity of the branched DNA (bDNA) signal
amplification technique for the detection of multiple rat CYPs from
hepatocellular RNA. Oligonucleotide probe sets were designed to various
chemically inducible rat CYP mRNA transcripts, including CYP1A1,
CYP1A2, CYP2B1/2, CYP2E1, CYP3A1/23, and CYP4A2/3. The robustness of
the bDNA assay was assessed with the CYP2B1/2-specific probe set, and
total RNA was isolated from control and phenobarbital (PB)-treated
rats. Analysis of these RNA samples by bDNA signal amplification
resulted in a linear quantifiable range of RNA detection that spanned
three orders of magnitude (0.1-100 µg of total RNA). The fidelity of
the bDNA assay was evaluated within a single assay and between assays
where repeated measurements of a single sample were reproduced
reliably. The specificity of individual CYP probe sets was evaluated
with five typical CYP-inducing chemicals on the expression of specific
hepatic CYP mRNA transcripts. Male Sprague-Dawley rats were
administered 3-methylcholanthrene, PB, isoniazid,
pregnenolone-16
-carbonitrile, or clofibric acid to induce
transcription of CYP1A1, CYP1A2, CYP2B1/2, CYP2E1, CYP3A1/23, and
CYP4A2/3 mRNA, respectively. Analysis of chemical-induced differences in gene expression by bDNA signal amplification indicated that 3-methylcholanthrene induced CYP1A1 and CYP1A2 mRNA levels 670- and 11-fold, respectively; PB induced CYP2B1/2 expression 71-fold;
pregnenolone-16-carbonitrile induced CYP3A1/23 expression 34-fold;
and clofibric acid induced CYP4A2/3 expression 4.7-fold. Overall, these
data support the use of bDNA signal amplification technology as a
robust, reproducible, and efficient means of monitoring the
differential expression of multiple isoforms of the CYP enzyme family.
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J. M. Brady, N. J. Cherrington, D. P. Hartley, S. C. Buist, N. Li, and C. D. Klaassen Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats Drug Metab. Dispos., July 1, 2002; 30(7): 838 - 844. [Abstract] [Full Text] [PDF]
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S. W. Luckey, M. Taylor, B. P. Sampey, R. I. Scheinman, and D. R. Petersen 4-Hydroxynonenal Decreases Interleukin-6 Expression and Protein Production in Primary Rat Kupffer Cells by Inhibiting Nuclear Factor-kappa B Activation J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 296 - 303. [Abstract] [Full Text] [PDF]
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D. R. Johnson and C. D. Klaassen Regulation of Rat Multidrug Resistance Protein 2 by Classes of Prototypical Microsomal Enzyme Inducers That Activate Distinct Transcription Pathways Toxicol. Sci., June 1, 2002; 67(2): 182 - 189. [Abstract] [Full Text] [PDF]
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N. Li, D. P. Hartley, N. J. Cherrington, and C. D. Klaassen Tissue Expression, Ontogeny, and Inducibility of Rat Organic Anion Transporting Polypeptide 4 J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 551 - 560. [Abstract] [Full Text] [PDF]
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S. C. N. Buist, N. J. Cherrington, S. Choudhuri, D. P. Hartley, and C. D. Klaassen Gender-Specific and Developmental Influences on the Expression of Rat Organic Anion Transporters J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 145 - 151. [Abstract] [Full Text] [PDF]
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N. R. Vansell and C. D. Klaassen Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation Drug Metab. Dispos., March 1, 2002; 30(3): 240 - 246. [Abstract] [Full Text] [PDF]
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G. L. Guo, D. R. Johnson, and C. D. Klaassen Postnatal Expression and Induction by Pregnenolone-16alpha -Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver Drug Metab. Dispos., March 1, 2002; 30(3): 283 - 288. [Abstract] [Full Text] [PDF]
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D. R. Johnson, S. S. M. Habeebu, and C. D. Klaassen Increase in Bile Flow and Biliary Excretion of Glutathione-Derived Sulfhydryls in Rats by Drug-Metabolizing Enzyme Inducers Is Mediated by Multidrug Resistance Protein 2 Toxicol. Sci., March 1, 2002; 66(1): 16 - 26. [Abstract] [Full Text] [PDF]
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A. L. Slitt, N. J. Cherrington, D. P. Hartley, T. M. Leazer, and C. D. Klaassen Tissue Distribution and Renal Developmental Changes in Rat Organic Cation Transporter mRNA levels Drug Metab. Dispos., February 1, 2002; 30(2): 212 - 219. [Abstract] [Full Text] [PDF]
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N. J. Cherrington, D. P. Hartley, N. Li, D. R. Johnson, and C. D. Klaassen Organ Distribution of Multidrug Resistance Proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and Hepatic Induction of Mrp3 by Constitutive Androstane Receptor Activators in Rats J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 97 - 104. [Abstract] [Full Text] [PDF]
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G. L. Guo, S. Choudhuri, and C. D. Klaassen Induction Profile of Rat Organic Anion Transporting Polypeptide 2 (oatp2) by Prototypical Drug-Metabolizing Enzyme Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 206 - 212. [Abstract] [Full Text] [PDF]
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 A. N. Player, L.-P. Shen, D. Kenny, V. P. Antao, and J. A. Kolberg Single-copy Gene Detection Using Branched DNA (bDNA) In Situ Hybridization J. Histochem. Cytochem., May 1, 2001; 49(5): 603 - 612. [Abstract] [Full Text]
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