ABSTRACT
Bioassay-directed fractionation with a Salmonella/microsomal assay against the food borne mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was used to identify antimutagenic components of hops. Hops pellets extracted with diethylether showed antimutagenic activity against mutations induced by IQ. Fractionation of the diethylether extract (DE) by column chromatography, followed by semi-preparative HPLC yielded two fractions (E4b and E4d) with strong antimutagenic activity against IQ induced mutations. Separation of fraction E4b resulted in inactive fractions, while fraction E4d has been identified to be xanthohumol. In mammalian test system with human hepatoma HepG2 cells fraction E4d at 10mug/ml completely prevented formation of IQ induced DNA damage. These results indicate that xanthohumol is a very promising potential protective agent against genotoxicity of food borne carcinogens, which warrants further investigation.
Subject(s)
Antimutagenic Agents/pharmacology , Humulus/chemistry , Plant Extracts/pharmacology , Propiophenones/pharmacology , 4-Nitroquinoline-1-oxide/toxicity , Animals , Antimutagenic Agents/chemistry , Antimutagenic Agents/isolation & purification , Biological Assay/methods , Cell Line, Tumor , DNA Damage , Ether/chemistry , Flavonoids , Humans , Microsomes , Mutagens/pharmacology , Plant Extracts/isolation & purification , Propiophenones/isolation & purification , Quinolines/toxicity , Rats , Salmonella/chemistryABSTRACT
Various types of proteinases are implicated in the malignant progression of human and animal tumors. Proteinase inhibitors may therefore be useful as therapeutic agents in anti-invasive and anti-metastatic treatment. The aims of this study were (1) to estimate the relative importance of proteinases in B16 cell invasion in vitro using synthetic, class-specific proteinase inhibitors and (2) to assess the inhibitory effect of some naturally occurring cysteine proteinase inhibitors. Serine proteinase inhibitor reduced invasiveness by up to 24%, whereas inhibition of aspartic proteinases reduced invasion by 11%. Synthetic inhibitors of cysteine proteinases markedly impaired invasion: cathepsin B inhibitors, particularly Ca-074Me, inhibited invasion from 20-40%, whereas cathepsin L inhibitor Clik 148 reduced invasion by 11%. The potato cysteine proteinase inhibitor PCPI 8.7 inhibited invasion by 21%, whereas another potato inhibitor, PCPI 6.6, and the mushroom cysteine proteinase inhibitor clitocypin had no effects. As the inhibitors that inhibited cathepsin B were in general more efficient at impairing the invasiveness, we conclude that of the two cysteine proteinases, cathepsin B plays a more important role than cathepsin L in murine melanoma cell invasion.