PMID- 8187072
OWN - NLM
STAT- MEDLINE
DCOM- 19940621
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 54
IP  - 11
DP  - 1994 Jun 1
TI  - Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its 
      reduced metabolite in rats.
PG  - 2878-86
AB  - 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.
FAU - Prough, R A
AU  - Prough RA
AD  - Department of Biochemistry, University of Louisville School of Medicine, Kentucky 
      40292.
FAU - Webb, S J
AU  - Webb SJ
FAU - Wu, H Q
AU  - Wu HQ
FAU - Lapenson, D P
AU  - Lapenson DP
FAU - Waxman, D J
AU  - Waxman DJ
LA  - eng
GR  - CA43839/CA/NCI NIH HHS/United States
GR  - DK33765/DK/NIDDK NIH HHS/United States
GR  - ES04244/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (RNA, Messenger)
RN  - 459AG36T1B (Dehydroepiandrosterone)
RN  - 53-59-8 (NADP)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 95PS51EMXY (Androstenediol)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.3.3.- (palmitoyl CoA oxidase)
SB  - IM
MH  - Androstenediol/*pharmacology
MH  - Animals
MH  - Catalase/*biosynthesis
MH  - Cytochrome P-450 Enzyme System/*biosynthesis
MH  - Dehydroepiandrosterone/analogs & derivatives/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Induction
MH  - Male
MH  - Microbodies/*enzymology
MH  - Microsomes, Liver/*enzymology
MH  - NADP/biosynthesis
MH  - Oxidoreductases/*biosynthesis
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
EDAT- 1994/06/01 00:00
MHDA- 1994/06/01 00:01
CRDT- 1994/06/01 00:00
PHST- 1994/06/01 00:00 [pubmed]
PHST- 1994/06/01 00:01 [medline]
PHST- 1994/06/01 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1994 Jun 1;54(11):2878-86.