Detection of Endogenous Malondialdehyde-Deoxyguanosine Adducts in Human Liver

Ak, Chaudhary; Nokubo, Munetaka; Reddy, G. Ramachandra; Yeola, Suresh; Jd, Morrow; Ia, Blair; Marnett, L.J.

doi:10.1126/science.8079172

Cited by 395 publications

(265 citation statements)

References 26 publications

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“…A very similar difference in M 1 G levels between pre-and post-treatment samples was observed in patients who received 450 or 1800 mg curcumin. For orientation, these values compare with a mean of 4.5 adducts per 10 7 nucleotides reported in normal rat liver (Sharma et al, 2001a) for orientation, these values compose with a mean of 4.5 adducts per 10 7 nucleotides reported in rat liver (Sharma et al, 2001a) and with 5-10 adducts per 10 7 nucleotides in healthy liver tissue from humans (Chaudhary et al, 1994). The fact that levels were consistently increased post-treatment irrespective of curcumin dose is counterintuitive in the light of the absence of curcuminderived species in the livers of patients on the low dose, and its presence at extremely low levels in only one of the patients on 3600 g curcumin (see above).…”

Section: Resultssupporting

confidence: 53%

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration

et al. 2004

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Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450 -3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M 1 G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.

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Section: Resultssupporting

confidence: 53%

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration

et al. 2004

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“…1) (13). M 1 G has been detected in several healthy human tissues including normal human colorectal mucosa and in human colorectal adenomas (14)(15)(16)(17)(18).…”

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confidence: 99%

Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde

VanderVeen

Hashim

Shyr

et al. 2003

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

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Instability of repetitive sequences is a hallmark of human cancer, and its enhancement has been linked to oxidative stress. Malondialdehyde is an endogenous product of oxidative stress that reacts with guanine to form the exocyclic adduct, pyrimido[1,2-␣]purin-10(3H)-one (M1G). We used site-specifically modified single-and double-stranded vectors to investigate the mutagenic potential of M1G in bacteria and mammalian cells. M1G induced frameshift mutations (؊1 and ؊2) when positioned in a reiterated (CpG)4 sequence but not when positioned in a nonreiterated sequence in Escherichia coli and in COS-7 cells. The frequency of frameshift mutations was highest when M1G was placed at the third G in the sequence. M1G induced base pair substitutions at comparable frequencies in both sequence contexts in COS-7 cells. These studies indicate that M1G, an endogenously generated product of oxidative stress, induces sequence-dependent frameshift mutations and base pair substitutions in bacteria and in mammalian cells. This finding suggests a potential role for the M1G lesion in the induction of mutations commonly associated with human diseases.

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“…They are reactive electrophiles that form adducts to protein and DNA that have been detected in tissues from healthy human beings and individuals with various diseases (2)(3)(4)(5)(6). Consequently, aldehydes modulate the activities of numerous proteins, induce mutations, and alter cell cycle progression (7)(8)(9)(10)(11)(12).…”

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confidence: 99%

IκB Kinase, a Molecular Target for Inhibition by 4-Hydroxy-2-nonenal

Kozak

Marnett

2001

Journal of Biological Chemistry

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186

153

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Aldehydes are products and propagators of oxidative stress (1). They are reactive electrophiles that form adducts to protein and DNA that have been detected in tissues from healthy human beings and individuals with various diseases (2-6). Consequently, aldehydes modulate the activities of numerous proteins, induce mutations, and alter cell cycle progression (7-12). For example, malondialdehyde, a major carbonyl product of lipid peroxidation, is mutagenic and carcinogenic and induces cell cycle arrest at the G 1 /S and G 2 /M checkpoints (7). The G 1 /S arrest in human colon and lung cancer cells (RKO and H1299, respectively) is caused by induction of the cyclin-dependent kinase inhibitor, p21, whereas the G 2 /M arrest appears to be due to a reduction in the level of the cdc2 kinase. Thus, alteration of gene expression triggered by protein or DNA damage may contribute to the range of biological effects exerted by aldehydes.A panoply of pathophysiological responses is also exerted by 4-hydroxynonenal (HNE), 1 the major toxic product of lipid peroxidation (1). HNE reacts with sulfhydryl and amino groups and leads to inactivation of DNA polymerases, dehydrogenases, and various transporters, inter alia (13). It also causes cell cycle arrest and apoptosis (8 -10). HNE treatment of cells alters the expression of several transcription factors including c-Myc (12), c-Myb (14), and c-Jun (15), suggesting that it may have more global effects on protein expression and cell function. The induction of c-Jun by HNE is associated with activation of JNK kinase and p38 kinase, perhaps by H 2 O 2 modulation of upstream signaling pathways (15, 16).A major signaling pathway associated with inflammation and oxidative stress is mediated by the transcription factor NF-B (17-19). NF-B consists of heterodimers of two polypeptides, p50 and p65, which are members of a family of proteins related to the proto-oncogene c-rel (20, 21). Inactive NF-B is located in the cytosol, bound to its inhibitory protein, IB. Dissociation of NF-B from IB is a critical step in NF-B activation that leads to translocation of NF-B to the nucleus, enabling DNA binding and transactivation (22). This process is triggered by sequential phosphorylation and ubiquitination of IB␣, followed by digestion of the ubiquinated protein by the proteasome (23-25). The enzyme that catalyzes the ubiquitination of phosphorylated IB is constitutively active. Hence, in most cases, the key event for NF-B activation is phosphorylation of two serine residues at the N terminus of IB by IB kinase (IKK) (23,24).We report here that treatment of RKO and H1299 cells with HNE leads to a dramatic loss of DNA binding and transcriptional activation by NF-B in cells treated with tetradecanoylphorbol acetate (TPA) and ionomycin (IM). The loss of NF-B activity is due to stabilization to the IB␣-NF-B complex, which results from a decrease in the rate of turnover of IB␣. The prevention of IB␣ turnover is attributable to the inhibition of IKK caused by direct reaction with HNE. These findings indica...

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Detection of Endogenous Malondialdehyde-Deoxyguanosine Adducts in Human Liver

Cited by 395 publications

References 26 publications

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration

Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde

IκB Kinase, a Molecular Target for Inhibition by 4-Hydroxy-2-nonenal

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