Linked Life Data

9000567

Source:http://linkedlifedata.com/resource/pubmed/id/9000567

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1997-2-11
pubmed:abstractText
Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the antioxidant responsive element (5-14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
57
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
272-8
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:9000567-Animals, pubmed-meshheading:9000567-Anticarcinogenic Agents, pubmed-meshheading:9000567-Chloramphenicol O-Acetyltransferase, pubmed-meshheading:9000567-Enzyme Induction, pubmed-meshheading:9000567-Female, pubmed-meshheading:9000567-Genes, Regulator, pubmed-meshheading:9000567-Glutathione, pubmed-meshheading:9000567-Humans, pubmed-meshheading:9000567-Liver, pubmed-meshheading:9000567-Mammary Neoplasms, Experimental, pubmed-meshheading:9000567-Mice, pubmed-meshheading:9000567-Mice, Inbred BALB C, pubmed-meshheading:9000567-NAD(P)H Dehydrogenase (Quinone), pubmed-meshheading:9000567-Organ Culture Techniques, pubmed-meshheading:9000567-RNA, Messenger, pubmed-meshheading:9000567-Thiocarbamates, pubmed-meshheading:9000567-Thiocyanates, pubmed-meshheading:9000567-Transfection, pubmed-meshheading:9000567-Tumor Cells, Cultured
pubmed:year
1997
pubmed:articleTitle
Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes.
pubmed:affiliation
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't