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PubMed2005

Effects of suberoylanilide hydroxamic acid and trichostatin A on induction of cytochrome P450 enzymes and benzo[a]pyrene DNA adduct formation in human cells.

In this study, we investigated the effects of histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) on the metabolism of polycyclic aromatic hydrocarbons (PAH) in human mammary carcinoma derived MCF-7 cells in culture. Benzo[a]pyrene (B[a]P) induces cytochrome P450 (CYP) 1A1, CYP1B1 and other xenobiotic metabolizing enzymes. Results from our study indicated a significant increase in CYP activity in comparison to vehicle control in cells treated with SAHA or TSA as measured by ethoxyresorufin-O-deethylase assay. However, co-treatment with 1.0 microM SAHA and BP, reduced the mRNA levels of CYP1B1 relative to B[a]P alone. When co-treated with 1.0 microM TSA and BP, a reduction in the mRNA levels of both CYP1A1 and CYP1B1 was observed relative to BP alone. We further investigated to ascertain if the differential expression and activity of CYP1A1 and CYP1B1 influenced levels of B[a]P DNA adduct formation. MCF-7 cells co-treated with B[a]P and SAHA or TSA formed DNA adducts, although no significant differences in levels of DNA binding were revealed. These results suggest that while CYP enzyme activity and gene expression were affected by the HDAC inhibitors SAHA and TSA, they had no apparent influence on B[a]P DNA binding.

Antineoplastic Agents↗
PubMed2004

Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes.

Zerumbone (ZER), a sesquiterpene compound occurring in tropical ginger Zingiber zerumbet Smith, has been implicated as one of the promising chemopreventive agents against colon and skin cancer. In the present study, we investigated the phase II detoxification enzymes induction of ZER using a cultured rat normal liver epithelial cell line. Exposure of RL34 cells to ZER resulted in the significant induction of glutathione S-transferase, while the reduced analogues of ZER (alpha-humulene and 8-hydroxy-alpha-humulene) did not show any inducing effect. Therefore, the electrophilic property, characterized by the reactivity with intracellular nucleophiles including protein sulfhydryls as well as low molecular weight thiols, at the 8-position alpha,beta-unsaturated carbonyl group plays an important role in the induction of phase II enzymes. ZER induced nuclear localization of the transcription factor Nrf2 that binds to antioxidant response element (ARE) of the phase II enzyme genes, suggesting that ZER is a potential activator of the Nrf2/ARE-dependent detoxification pathway. This is consistent with the observation that ZER potentiated the gene expression of several Nrf2/ARE-dependent phase II enzyme genes, including gamma-glutamylcysteine synthetase, glutathione peroxidase, and hemeoxygenase-1. The present study also implied the antioxidant role of this detoxification system activation by ZER in the neutralization of lipid peroxidation in hepatocytes, providing a new insight for cancer prevention.

Animals↗
PubMed2001

Forging the links between metabolism and carcinogenesis.

Metabolism plays important roles in chemical carcinogenesis, both good and bad. The process of carcinogen metabolism was first recognized in the first half of the twentieth century and developed extensively in the latter half. The activation of chemicals to reactive electrophiles that become covalently bound to DNA and protein was demonstrated by Miller and Miller [Cancer 47 (1981) 2327]. Today many of the DNA adducts formed by chemical carcinogens are known, and extensive information is available about pathways leading to the electrophilic intermediates. Some concepts about the stability and reactivity of electrophiles derived from carcinogens have changed over the years. Early work in the field demonstrated the ability of chemicals to modulate the metabolism of carcinogens, a phenomenon now described as enzyme induction. The cytochrome P450 enzymes play a prominent role in the metabolism of carcinogens, both in bioactivation and detoxication. The conjugating enzymes can also play both beneficial and detrimental roles. As an example of a case in which several enzymes affect the metabolism and carcinogenicity of a chemical, aflatoxin B1 (AFB1) research has revealed insight into the myriad of reaction chemistry that can occur even with a 1s half-life for a reactive electrophile. Further areas of investigation involve the consequences of enzyme variability in humans and include areas such as genomics, epidemiology, and chemoprevention.

Aflatoxin B1↗
PubMed2002

Characterization of cDNAs encoding diacylglycerol acyltransferase from cultures of Brassica napus and sucrose-mediated induction of enzyme biosynthesis.

cDNAs encoding acyl-CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20), designated BnDGAT1 and BnDGAT2, were obtained from a microspore-derived cell suspension culture of oilseed rape (Brassica napus L. cv Jet Neuf). BnDGAT2 shares a very high level of identity with BnDGAT1, but is a smaller protein lacking the relatively hydrophilic N-terminal segment found in BnDGAT1. Both transcripts were produced in the cell suspension cultures and the cDNAs were functionally expressed in transformed yeast (Pichia pastoris) cells. Sucrose-mediated changes in triacylglycerol (TAG) metabolism and expression of BnDGAT1 were examined in the cell suspension cultures following transfer of cells from media containing 6% (w/v) sucrose to media containing 14% sucrose. TAG content and DGAT activity of the cells increased transiently within the first 12 h after transfer (HAT). The rapid decline in TAG content observed at 12 HAT was inversely related to an increase in TAG lipase (EC 3.1.1.3) activity. The transient increases in TAG content and DGAT activity correlated with the elevated amounts of BnDGAT1 polypeptide. Transcript levels were also induced, but levels of mRNA encoding BnDGAT1 were not tightly correlated with DGAT activity and amount of polypeptide suggesting some control of expression at the post-transcriptional level. In general, the rapid changes in TAG content were closely associated with the changes in the activity of TAG-metabolizing enzymes and expression of BnDGAT1.

Acyltransferases↗
PubMed2003

Cell cross-talk mediates PPARalpha null hepatocyte proliferation after peroxisome proliferator exposure.

Peroxisome proliferator activated receptor(alpha) (PPARalpha) mediates the liver's responses to peroxisome proliferator compounds. These responses include induction of specific hepatic enzymes, peroxisome proliferation and hepatocyte proliferation. PPARalpha null mice, which lack receptor in all cells of the body, do not respond to peroxisome proliferators, indicating that hepatocellular proliferation and other responses require the presence of this receptor in at least some cells. To determine if PPARalpha is required specifically in hepatocytes for each response, we used hepatocyte transplantation to generate chimeric livers composed of PPARalpha null and positive hepatocytes in PPARalpha null or positive hosts. Upon exposure to a peroxisome proliferator, peroxisome proliferation and enzyme induction were restricted to receptor positive hepatocytes, indicating that these responses are cell autonomous with respect to hepatocyte receptor status. However, both PPARalpha null and positive hepatocytes in chimeric livers displayed elevated DNA synthesis regardless of host receptor status, as long as at least some hepatocytes contained receptor. These findings indicate that the mitogenic response to peroxisome proliferators does not require PPARalpha in all hepatocytes.

Animals↗
PubMed1993

Thermoinductive Regulation of Gibberellin Metabolism in Thlaspi arvense L. (II. Cold Induction of Enzymes in Gibberellin Biosynthesis).

Vernalization of Thlaspi arvense L. results in the alteration of gibberellin (GA) metabolism such that the metabolism and turnover of the GA precursor ent-kaur-16-en-19-oic acid (kaurenoic acid) is dramatically increased. This cold-induced change in GA metabolism is restricted to the shoot tip, the site of perception of cold in this species (J.P. Hazebroek, J.D. Metzger [1990] Plant Physiol 94: 157-165). In the present report additional biochemical information about the nature of this low-temperature-regulated process is provided. The endogenous levels of kaurenoic acid in leaves and shoot tips of plants were estimated by combined gas chromatography-chemical ionization mass spectrometry at various times after 4 weeks of vernalization at 6[deg]C. The endogenous levels in shoot tips declined 10-fold by 2 d after the plants were returned to 21[deg]C; this decline continued such that there was nearly 50-fold less kaurenoic acid by 10 d after the end of vernalization. No effect of vernalization on the endogenous levels of kaurenoic acid in leaves was observed. An in vitro enzyme assay was developed to monitor changes in the ability of tissues to convert kaurenoic acid to ent-7[alpha]-hydroxykaur-16-en-19-oic acid (7-OH kaurenoic acid). The activity of this enzyme rapidly increased in microsomal extracts from shoot tips following the end of vernalization. No thermoinduced increase in activity was observed in leaves. The enzymic oxidation of ent-kaurene to ent-kaurenol was also induced in shoot tips by vernalization. However, this reaction does not appear to be rate limiting for GA biosynthesis, because substantial amounts of kaurenoic acid accumulated in noninduced shoot tips. These results corroborate our hypothesis that the conversion of kaurenoic acid to 7-OH kaurenoic acid is the primary step in GA metabolism regulated by vernalization in Thlaspi shoot tips.

Journal Article↗
PubMed1982

Abscisic Acid stimulation of suberization : induction of enzymes and deposition of polymeric components and associated waxes in tissue cultures of potato tuber.

Effect of abscisic acid (ABA) on suberization of potato (Solanum tuberosum var. Russet-Burbank) tuber tissue culture was studied by measuring deposition of suberin components and the level of certain key enzymes postulated to be involved in suberization. ABA treatment resulted in a 3-fold increase in the polymeric aliphatic components of suberin and a 4-fold increase in the polymeric aromatic components. Hydrocarbons and fatty alcohols, two components characteristic of waxes associated with potato suberin, increased 9- and 5-fold, respectively, as a result of ABA treatment. Thus, the deposition of the polymeric aliphatics and aromatics as well as waxes, all of which have been postulated to be components of suberized cell walls, was markedly stimulated by ABA. omega-Hydroxy-fatty acid dehydrogenase which showed a rather high initial level of activity increased only 60% due to ABA treatment. Phenylalanine ammonia-lyase activity reached a maximum at a 5-fold level after 4 days in the ABA medium, whereas the control showed only a 3-fold increase. ABA treatment also resulted in a dramatic (7-fold) increase in an isozyme of peroxidase which has been specifically associated with suberization. Thus, ABA appears to induce certain key enzymes which are most probably involved in suberization.

Journal Article↗
PubMed1977

Insulin antagonism of dexamethasone-induced increase or argininosuccinate synthetase and argininosuccinate lyase activities in cultured fetal rat liver.

In fetal rat liver explants maintained in organ culture, the addition of dexamethasone (4.6 X 10(-6)M) produced a 2- to 3-fold increase in the activity of argininosuccinate synthetase and in argininosuccinate lyase after 24 and 48 h of incubation. Insulin (1.8 X 10(-6)M) alone had no effect on the enzyme activities, but when incubated together with dexamethasone, it abolished the dexamethasone-induced increase of argininosuccinate synthetase and inhibited the argininosuccinate lyase activity by 80%, at 24 h. At 48 h, the inhibition of both enzyme activities was 68%. The antagonistic effect of insulin on the dexamethasone action is discussed in relation to the mechanism of perinatal enzyme induction. Hyperinsulinemia may interfere with the development of enzyme systems during the perinatal period. This could have relevance in the care of infants of diabetic mothers.

Animals↗
PubMed1991

Interference by anti-C5a monoclonal antibodies with the binding of C5a to cellular receptors and the induction of enzyme release from granulocytes.

A sandwich ELISA based on monoclonal antibodies (MAb) for the quantification of rabbit C5a is only modestly influenced by the presence of MAb 4A3A9, which reacts with an epitope on C5a different from those of MAbs used in the sandwich ELISA. Incubation of rabbit or human granulocytes with C5a in the presence of MAb 4A3A9 results in a less pronounced decrease of the C5a concentration as compared to the concentration measured in the absence of MAb. We interpret the results to indicate an interference of MAb 4A3A9 with the binding of C5a to and/or the dissociation of C5a from its cellular receptor. MAb 4A3A9 is the least effective (25.4% inhibition) among anti-C5a MAbs in inhibiting C5a-induced beta-glucuronidase release from neutrophils. Together, these findings may indicate that a C5a-MAb complex is still able to induce a C5a effect even if MAb does interfere with the binding of ligand to the receptor.

Animals↗
PubMed1989

Liver enzyme changes in a guinea-pig model of facial eczema (sporidesmiotoxicosis).

Sporidesmin, a hepatotoxin from Pithomyces chartarum, is responsible for facial eczema in ruminants. In an attempt to clarify the biochemical processes supporting sporidesmin toxicity and response of the liver, haematology, plasma biochemistry and liver enzyme changes were monitored for 21 days in a model for facial eczema resulting from a single intraperitoneal injection of 2.8 mg/kg BW sporidesmin to guinea pigs. Most plasma disturbances were observed 8 days after administration and accounted for starvation, liver cytolysis, and cholestasis or liver enzyme induction. Alterations of hepatic enzyme activities were intense with a maximum increase on days 2 for alkaline phosphatases (ALP) and 8 for gamma-glutamyltransferase (GGT), and a maximum decrease on day 21 for aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). Comparison of liver and plasma enzyme changes indicates that GGT was the most reliable and significant plasma indicator of sporidesmin-associated liver alterations. Moreover, this study points out the validity of the one-dose intoxicated guinea-pig model for research on sporidesmin biochemical toxicity and pathobiology of facial eczema.

Alanine Transaminase↗