Metabolism of Xenobiotics in Hepatocyte Nodules

Eriksson, Lennart C.; Blanck, Agneta; Bock, Karl Walter; Mannervik, Bengt

doi:10.1177/019262338701500104

Cited by 26 publications

(8 citation statements)

References 39 publications

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“…mEH has been shown in numerous rodent hepatocarcinogenesis studies to be elevated in nodules using both biochemical (57,58) and immunohistochemical methods (59,60). Although tumorbearing liver in this study showed an increase over previusly cited control values for rainbow trout using the same substrates [2.70-3.38 cEH and 0.78-0.98 nmol/min/mg protein mEH (26)], we saw no significant increase over control activity in this study.…”

Section: Chlorodinitrobenzidine (Cdnb) or Ethacrynic Acid)contrasting

confidence: 67%

Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss

Parker

Laurén²,

Hammock

et al. 1993

Carcinogenesis

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Biochemical and histochemical studies were conducted in aflatoxin B1-induced liver tumors in adult rainbow trout. Specific activities of the phase I enzymes, ethoxyresorufin-O-deethylase (EROD), microsomal and cytosolic epoxide hydrolase (mEH and cEH), aldehyde dehydrogenase (ALDH) and DT-diaphorase, and the phase II enzymes, gamma-glutamyltransferase (gamma-GT), glutathione transferase (GST) and uridine diphosphoglucuronyl transferase (UDPGT) were measured. Cryostat sections of tumor and surrounding liver from the same cohorts were analyzed immunohistochemically for cytochrome P450IA1 and histochemically for ALDH (benzaldehyde and hexanal), DT-diaphorase, gamma-GT and uridine diphosphoglucuronyl dehydrogenase (UDPGdH). In tumor tissues, the largest biochemical changes were found with benzaldehyde dehydrogenase, where activity increased from undetectable levels to 7.4 nmol/min/mg protein, and gamma-GT, where activity increased 12-fold over controls. Increases in other enzymes ranged from 1.26 to 2.84 times that of control liver, except EROD, which decreased, and cEH and mEH, which were unchanged. Histochemical analyses showed the induction of ALDH, gamma-GT, DT-diaphorase and UDPGdH, and the depression of cytochrome P450IA1 in hepatic neoplasms. In addition, marker enzyme histochemistry of neoplasms revealed heterogeneous populations of hepatocytes and absence of necrotic areas.

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Section: Chlorodinitrobenzidine (Cdnb) or Ethacrynic Acid)contrasting

confidence: 67%

Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss

Parker

Laurén²,

Hammock

et al. 1993

Carcinogenesis

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“…There is an established literature showing a general reduction in the activities of P450 enzymes in hepatic nodules [33]. Consistent with this, we observed a general trend toward reduced peptide abundance in the placebo group foci relative to the control liver samples.…”

Section: Resultssupporting

confidence: 89%

Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma

et al. 2017

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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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“…In terms of the physiological function, it appears relevant that class Pi GSTs are often expressed in response to chemical insults, as exemplified by the rat hepatocyte nodule model (38). GST P1-i is also produced at high levels in many tumor cells (19)(20)(21)39).…”

Section: Discussionmentioning

confidence: 99%

Detoxication of base propenals and other alpha,beta-unsaturated aldehyde products of radical reactions and lipid peroxidationby human glutathione transferases.

Berhane

Widersten

Engström

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

398

224

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Radiation and chemical reactions that give rise to free radicals cause the formation of highly cytotoxic base propenals, degradation products of DNA. Human glutathione transferases (GSTs; RX:glutathione R-transferase, EC 2.5.1.18) of classes Alpha, Mu, and Pi were shown to promote the conjugation of glutathione with base propenals and related alkenes. GST P1-i was particularly active in catalyzing the reactions with the propenal derivatives, and adenine propenal was the substrate giving the highest activity. The catalytic efficiency of GST P1-i with adenine propenal (kat/K. = 7.7 x 105 M-1's-) is the highest so far reported with any substrate for this enzyme. In general, GST Al-i and GST Mi-i, in contrast to GST P1-i, were more active with 4-hydroxyalkenals (products of lipid peroxidation) than with base propenals. The adduct resulting from the Michael addition of glutathione to the alkene function of one of the base propenals (adenine propenal) was identified by mass spectrometry. At the cellular level, GST P1-i was shown to provide protection against a,4-unsaturated aldehydes. GST Pi-i added to the culture medium of HeLa cells augmented the protective effect of glutathione against the toxicity of adenine propenal and thymine propenal. No protective effect ofthe enzyme was observed in the presence of the competitive inhibitor S-hexylglutathione. GST Pi-i introduced into Hep G2 cells by electroporation was similarly found to increase their resistance to acrolein. The results show that glutathione transferases may play an important role in cellular detoxication of electrophilic a,.-unsaturated carbonyl compounds produced by radical reactions, lipid peroxidation, ionizing radiation, and drug metabolism.

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Metabolism of Xenobiotics in Hepatocyte Nodules

Cited by 26 publications

References 39 publications

Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss

Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss

Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma

Detoxication of base propenals and other alpha,beta-unsaturated aldehyde products of radical reactions and lipid peroxidationby human glutathione transferases.

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