Formation and Persistence of Isoniazid-DNA Adducts in Mouse Tissues

1987 ◽  
Vol 6 (2) ◽  
pp. 153-158 ◽  
Author(s):  
G.B. Maru ◽  
S. Bhide ◽  
R. Saffhill ◽  
P.J. O'Connor
Keyword(s):  
Dna Synthesis ◽  
Dna Adducts ◽  
Target Tissue ◽  
Dna Templates ◽  
Modified Dna ◽  
Mouse Tissues ◽  
Tissue Differences ◽  
Neonatal Administration

Further confirmation is provided to support the identity of the product formed by the in vitro eaction of isoniazid (INH) with cytosine as 4-deamino-4-isoniazidocytosine (INH-cytosine). Use of INH-treated mice, in which the tissue DNA is prelabelled by the neonatal administration of [3H]-deoxycytidine, has revealed the presence of two other DNA products in addition to INHytosine. Tissue differences in the persistence of these three DNA products suggest the presence of repair eactions for certain adducts. These processes and the effects of hepatotoxicity lead to a selective etention of adducts in the DNA of lung which is the target tissue for INH-carcinogenicity in mice. INH-modified DNA templates are weakly promutagenic during in vitro DNA synthesis. The implications of these observations for the role of INH as an initiating agent and for the pecies differences in its carcinogenicity are discussed.

STEROID HORMONE METABOLISM IN RESPONSIVE TISSUES IN VITRO

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S279-S294 ◽  
Author(s):  
Paul Robel
Keyword(s):  
Steroid Hormone ◽  
Physiological Activity ◽  
Physiological State ◽  
Target Cells ◽  
Target Tissue ◽  
Hormone Metabolism ◽  
Metabolizing Enzymes ◽  
Relationship Of

ABSTRACT Of the information available on steroid hormone metabolism in responsive tissues, only that relating hormone metabolism to physiological activity is reviewed, i. e. metabolite activity in isolated in vitro systems, binding of metabolites to target tissue receptors, specific steroid hormone metabolizing enzymes and relationship of hormone metabolism to target organ physiological state. Further, evidence is presented in the androgen field, demonstrating 5α-reduced metabolites, formed inside the target cells, as active compounds. This has led to a consideration of testosterone as a »prehormone«. The possibility that similar events take place in tissues responding to progesterone is discussed. Finally, the role of hormone metabolism in the regulation of hormone availability and/or renewal in target cells is discussed. In this context, reference is made to the potential role of plasma binding proteins and cytosol receptors.

Different effects of DNA adducts induced by carcinogenic and noncarcinogenic azo dyes on in vitro DNA synthesis

1991 ◽  
Vol 179 (2) ◽  
pp. 817-823 ◽  
Author(s):  
Misaki Kojima ◽  
Masakuni Degawa ◽  
Yoshiyuki Hashimoto ◽  
Mariko Tada
Keyword(s):  
Dna Synthesis ◽  
Dna Adducts ◽  
Azo Dyes

scholarly journals Tissue-specific characterization of mitochondrial branched-chain keto acid oxidation using a multiplexed assay platform

2019 ◽  
Vol 476 (10) ◽  
pp. 1521-1537 ◽  
Author(s):  
Emma J. Goldberg ◽  
Katherine A. Buddo ◽  
Kelsey L. McLaughlin ◽  
Regina F. Fernandez ◽  
Andrea S. Pereyra ◽  
...  
Keyword(s):  
Acid Oxidation ◽  
Valuable Insight ◽  
Keto Acid ◽  
Isolated Mitochondria ◽  
Mouse Tissues ◽  
Branched Chain

Abstract Alterations to branched-chain keto acid (BCKA) oxidation have been implicated in a wide variety of human diseases, ranging from diabetes to cancer. Although global shifts in BCKA metabolism—evident by gene transcription, metabolite profiling, and in vivo flux analyses have been documented across various pathological conditions, the underlying biochemical mechanism(s) within the mitochondrion remain largely unknown. In vitro experiments using isolated mitochondria represent a powerful biochemical tool for elucidating the role of the mitochondrion in driving disease. Such analyses have routinely been utilized across disciplines to shed valuable insight into mitochondrial-linked pathologies. That said, few studies have attempted to model in vitro BCKA oxidation in isolated organelles. The impetus for the present study stemmed from the knowledge that complete oxidation of each of the three BCKAs involves a reaction dependent upon bicarbonate and ATP, both of which are not typically included in respiration experiments. Based on this, it was hypothesized that the inclusion of exogenous bicarbonate and stimulation of respiration using physiological shifts in ATP-free energy, rather than excess ADP, would allow for maximal BCKA-supported respiratory flux in isolated mitochondria. This hypothesis was confirmed in mitochondria from several mouse tissues, including heart, liver and skeletal muscle. What follows is a thorough characterization and validation of a novel biochemical tool for investigating BCKA metabolism in isolated mitochondria.

Cytochrome P-450 and Peroxidase Oxidize Detoxication Products of Carcinogenic Aristolochic Acids (Aristolactams) to Reactive Metabolites Binding to DNA in vitro

1995 ◽  
Vol 60 (12) ◽  
pp. 2189-2199 ◽  
Author(s):  
Marie Stiborová ◽  
Eva Frei ◽  
Heinz H. Schmeiser ◽  
Manfred Wiessler
Keyword(s):  
Dna Adducts ◽  
Microsomal Cytochrome ◽  
Aristolochic Acids ◽  
Nuclease P1 ◽  
Order Of Magnitude ◽  
Prostaglandin H ◽  
Cytochrome P 450

We report the analysis of DNA adducts formed from aristolactams I and II, which are the final metabolites derived from carcinogenic aristolochic acids in vivo, after their oxidation by microsomal cytochrome P-450 and horseradish peroxidase in vitro. DNA adducts were detected and quantified using the nuclease P1-enhanced variation of the 32P-postlabeling assay. Quantitative analysis revelead that the extent of modification of DNA by aristolactams activated by peroxidase was more than one order of magnitude higher than for activation by microsomal cytochrome P-450. Peroxidase catalyzes the formation of active oxygen in the presence of NADH, H2O2 and aristolactams. Aristolactams are also oxidized by mammalian peroxidase prostaglandin H synthase. The possible role of aristolactams in carcinogenesis induced by aristolochic acid is discussed.

scholarly journals A critical role for chromatin in mounting a synergistic transcriptional response to GAL4-VP16

1994 ◽  
Vol 14 (8) ◽  
pp. 5175-5181
Author(s):  
C Chang ◽  
J D Gralla
Keyword(s):  
Critical Role ◽  
Transcriptional Response ◽  
Dna Templates ◽  
Naked Dna ◽  
Promoter Dna

The role of chromatin in mounting a synergistic transcriptional response to GAL4-VP16 was investigated. Strong synergy was observed when chromatin templates were used in vitro. The synergy was severely reduced when naked DNA templates were transcribed. In vivo synergy was strong when nonreplicating templates were used. However, the use of replicating templates, which involved transient disruptions of chromatin, led to strong reductions in synergy. In both of these low-synergy responses, transcription levels were high. We infer that strong synergy has a requirement for chromatin that may be understood in terms of the competition between multiple activator molecules and histone cores for promoter DNA.

scholarly journals Emerging Links between Cadmium Exposure and Insulin Resistance: Human, Animal, and Cell Study Data

Toxics ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 63
Author(s):  
Aleksandra Buha ◽  
Danijela Đukić-Ćosić ◽  
Marijana Ćurčić ◽  
Zorica Bulat ◽  
Biljana Antonijević ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Study Data ◽  
Current Evidence ◽  
Target Tissue ◽  
Insulin Production ◽  
Β Cells ◽  
Glucose Levels ◽  
Human Animal

Recent research has helped clarify the role of cadmium (Cd) in various pathological states. We have demonstrated Cd involvement in pancreatic cancer, as well as the bioaccumulation of Cd in the pancreas. Bioaccumulation and increased toxicity suggest that Cd may also be involved in other pancreas-mediated diseases, like diabetes. Cd falls into the category of “hyperglycemic” metals, i.e., metals that increase blood glucose levels, which could be due to increased gluconeogenesis, damage to β-cells leading to reduced insulin production, or insulin resistance at target tissue resulting in a lack of glucose uptake. This review addresses the current evidence for the role of Cd, leading to insulin resistance from human, animal, and in vitro studies. Available data have shown that Cd may affect normal insulin function through multiple pathways. There is evidence that Cd exposure results in the perturbation of the enzymes and modulatory proteins involved in insulin signal transduction at the target tissue and mutations of the insulin receptor. Cd, through well-described mechanisms of oxidative stress, inflammation, and mitochondrial damage, may also alter insulin production in β-cells. More work is necessary to elucidate the mechanisms associated with Cd-mediated insulin resistance.

scholarly journals Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1

Science ◽  
2014 ◽  
Vol 346 (6213) ◽  
pp. 1127-1130 ◽  
Author(s):  
Renjing Wang ◽  
Nicole S. Persky ◽  
Barney Yoo ◽  
Ouathek Ouerfelli ◽  
Agata Smogorzewska ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Crystal Structures ◽  
Dna Adducts ◽  
Fanconi Anemia ◽  
Biochemical Data ◽  
Degenerative Diseases ◽  
Cross Link ◽  
Interstrand Cross Links ◽  
Cross Links

DNA interstrand cross-links (ICLs) are highly toxic lesions associated with cancer and degenerative diseases. ICLs can be repaired by the Fanconi anemia (FA) pathway and through FA-independent processes involving the FAN1 nuclease. In this work, FAN1-DNA crystal structures and biochemical data reveal that human FAN1 cleaves DNA successively at every third nucleotide. In vitro, this exonuclease mechanism allows FAN1 to excise an ICL from one strand through flanking incisions. DNA access requires a 5′-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3′ flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. FAN1’s mechanism of ICL excision is well suited for processing other localized DNA adducts as well.

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