Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its reduced metabolite in rats.
Dehydroepiandrosterone (DHEA) given to rodents in pharmacological doses induces several hepatic enzymes including cytochromes P4504A, NADPH:P450 oxidoreductase, palmitoyl coenzyme A oxidase, and other enzymes associated with the peroxisomal beta-oxidation pathway, leading to peroxisome proliferation and development of hepatocellular carcinoma in rodents. Comparison of the inductive potency of DHEA and other intermediates of the steroid biosynthetic path demonstrated that only DHEA, 5-ene-androstene-3 beta,17 beta-diol (ADIOL), and to a lesser extent, 17 alpha-hydroxypregnenolone, a precursor of DHEA, induce cytochromes P4504A protein and other enzymes associated with the peroxisome proliferative response in vivo. ADIOL exerted its inductive response at a somewhat lower dosage than DHEA, whereas ADIOL and DHEA both induced the microsomal enzymes (P4504A and its oxidoreductase) at somewhat lower dosages than those required to induce peroxisomal enzymes. Northern analysis demonstrated increases in the mRNAs encoding the cytochromes P4504A (> 20-fold) and NADPH:P450 oxidoreductase (> 10-fold) in the livers of DHEA- and ADIOL-treated rats. Run-on transcription analysis demonstrated that DHEA induces CYP4A gene expression 11-fold at the level of transcription initiation. Comparison of the responsiveness of individual rat CYP4A genes (4A1, 4A2, and 4A3) to DHEA and ADIOL in immature versus mature male rats revealed 2-3-fold higher levels of induced CYP4A1 and 4A3 mRNAs in immature rat livers. In contrast, hepatic CYP4A2 mRNA was induced to 6-10-fold higher levels in mature rats. No basal or significant inducible expression of mRNA for CYP4A1 and 4A3 was noted in rat kidney. Significant basal levels of kidney CYP4A2 mRNA were observed only in mature animals, where they were inducible by ADIOL and DHEA to a 3-5-fold greater extent than in the kidneys of immature rats. These studies demonstrate developmental differences in the responsiveness of CYP4A mRNA levels to DHEA and ADIOL in rat kidney and liver. Moreover, the striking inducibility of CYP4A protein and mRNAs, together with the increased rates of synthesis of nascent CYP4A mRNA transcripts in hepatic nuclei from DHEA-treated rats, establish that DHEA increases the expression of these microsomal enzymes at the transcriptional level.
Prough
R A
RA
Department of Biochemistry, University of Louisville School of Medicine, Kentucky 40292.
Webb
S J
SJ
Wu
H Q
HQ
Lapenson
D P
DP
Waxman
D J
DJ
D015114:Androstenediol / Q000494:pharmacology*; D000818:Animals; D002374:Catalase / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D008297:Male; D008830:Microbodies / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D015114:Androstenediol; D010088:Oxidoreductases; D002374:Catalase; C028427:palmitoyl CoA oxidase