Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fischer 344 rats readily develop liver cancer when exposed to aflatoxin B1 (AFB1) but dietary administration of the antioxidant ethoxyquin (EQ) provides protection against hepatocarcinogenesis. Chemoprotection by EQ is accompanied by the overexpression of enzymes which detoxify activated AFB1. Aflatoxin-protein adduct formation takes place following metabolism of AFB1 to the dialdehydic form of AFB1-dihydrodiol. The dialdehyde can be detoxified by reduction to a dialcohol through the catalytic actions of an enzyme present in the hepatic cytosol from rats fed EQ-containing diets; this metabolite is essentially undetectable in reaction mixtures that use hepatic cytosol from rats fed control diets. The enzyme responsible for catalyzing the formation of dihydroxy-aflatoxin B1 has been purified from the livers of rats fed on diets supplemented with EQ. It is a soluble monomeric protein with an approximate M(r) of 36,600. Besides its activity toward AFB1 this enzyme also catalyzes the reduction of the model substrate 4-nitrobenzaldehyde. Amino acid sequencing of cyanogen bromide-derived peptides obtained from this reductase indicated that it has not been characterized hitherto, at least not a molecular level. Therefore, this inducible enzyme has been designated aflatoxin B1-aldehyde reductase (AFB1-AR). The livers of adult rats administered dietary EQ contain at least 15-fold greater levels of AFB1-AR than the livers from rats fed control diets. Aflatoxin B1-AR was also found to be present in increased amounts in livers bearing preneoplastic nodules and in rat hepatoma, both of which are known to express increased resistance to AFB1. Kidney contains high constitutive levels of AFB1-AR and the administration of EQ increases its concentration in renal cytosol about 3-fold. Although AFB1-AR is present in trace amounts in rat lung it was not detected in brain and in neither tissue was it found to be induced by EQ. Evidence suggests that AFB1-AR is a previously unrecognized enzyme that could provide protection against the cytotoxic effects of aflatoxin B1 resulting from the formation of protein adducts. The relative importance of AFB1-AR and the glutathione-S-transferase Yc2 subunit in conferring resistance to aflatoxin B1 is discussed.
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PMID:Resistance to aflatoxin B1 is associated with the expression of a novel aldo-keto reductase which has catalytic activity towards a cytotoxic aldehyde-containing metabolite of the toxin. 839 32

We have shown previously that rapamycin, the canonical inhibitor of the mechanistic target of rapamycin (mTOR) complex 1, markedly inhibits the growth of focal lesions in the resistant hepatocyte (Solt-Farber) model of hepatocellular carcinoma (HCC) in the rat. In the present study, we characterized the proteome of persistent, pre-neoplastic focal lesions in this model. One group was administered rapamycin by subcutaneous pellet for 3 weeks following partial hepatectomy and euthanized 4 weeks after the cessation of rapamycin. A second group received placebo pellets. Results were compared to unmanipulated control animals and to animals that underwent an incomplete Solt-Farber protocol to activate hepatic progenitor cells. Regions of formalin-fixed, paraffin-embedded tissue were obtained by laser capture microdissection (LCM). Proteomic analysis yielded 11,070 unique peptides representing 2,227 proteins. Quantitation of the peptides showed increased abundance of known HCC markers (e.g., glutathione S-transferase-P, epoxide hydrolase, 6 others) and potential markers (e.g., aflatoxin aldehyde reductase, glucose 6-phosphate dehydrogenase, 10 others) in foci from placebo-treated and rapamycin-treated rats. Peptides derived from cytochrome P450 enzymes were generally reduced. Comparisons of the rapamycin samples to normal liver and to the progenitor cell model indicated that rapamycin attenuated a loss of differentiation relative to placebo. We conclude that early administration of rapamycin in the Solt-Farber model not only inhibits the growth of pre-neoplastic foci but also attenuates the loss of differentiated function. In addition, we have demonstrated that the combination of LCM and mass spectrometry-based proteomics is an effective approach to characterize focal liver lesions.
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PMID:Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma. 2819 61