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The Two-Step Concept of Intestinal Carcinogenesis
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Norman D. Nigro, Arthur W. Bull
The chemical modification of target tissue DNA by DMH has been studied in several laboratories. In 1972, Hawks et al. reported the formation of 7-methylguanine in the colonic DNA of DMH-treated mice at 6 and 24 hr after carcinogen treatment.35 In a later study, Rogers and Pegg reported the formation of several more methylated purines in colonic DNA of 14C-DMH-treated rats.36 The modified bases detected include, N-7- and O-6-methylguanines, as well as N-1-, N-7-, and N-3-methyladenines. Of the major modified bases, O6- methylguanine is considered to be deleterious, since it is promutagenic and its formation and persistance in a tissue correlate well with tumorigenesis.37,38
Genomic Instability During Aging of Postmitotic Mammalian Cells
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
It is of interest to compare the results from the indigenous 7-methylguanine studies in mice with those of oxidation damage to nuclear DNA of rat tissues. The total number of lesions per diploid genome (or per somatic cell) are of the same order of magnitude for liver and kidney tissues of the two species. For example, calculations indicate that there are 67,000 residues of 8-hydroxydeoxyguanosine per kidney cell in 4-month-old rats and 120,000 molecules of 7-methylguanine per kidney cell in 11-month-old mice. The higher levels of methyl adducts in mouse cells probably reflect the differences in rates of damage accumulation between the two species. For kidney tissue, it can be estimated that rats accumulate 8-hydroxydeoxyguanosine at 80 residues per day,135 whereas mice increase their steady-state levels of 7-methylguanine by 440 residues per day,128 or 5.5 times more rapidly than the oxidation damage. Whether these differences are due to species differences or to the nature of the lesions and their respective removal from DNA is not known. It is known that there are 12 sites of alkylation on DNA, but modification at N7-guanine occurs with the greatest frequency.72,125 In fact, 7-methylguanine represents roughly 70% of all lesions produced by simple direct-acting methylating agents in vivo and in vitro.115 Relatively speaking, 7-methylguanine is not removed as actively from DNA as some other methyl adducts and can persist for long times in vivo.72,125,128,179 By contrast, 8-hydroxydeoxyguanosine is only one of 20 known oxidative damages incurred by DNA in vivo.132,135 Its relative proportion to all other indigenous oxidative-DNA lesions in normal cells is not known, but the available data indicate that this modified nucleoside is very actively removed from DNA.68–71 Perhaps the most interesting difference in damage accumulation between the two rodents is the absence of an increase with age of 8-hydroxydeoxyguanosine in rat brain. Brain tissue is very active metabolically and consumes large amounts of oxygen136 which would seem to put brain genomes at risk for higher levels of oxidative damage, yet initial levels of 8-hydroxydeoxyguanosine are roughly the same as in other tissues, and moreover, did not change significantly with aging.135 Methyl adducts in brain DNA were fewer than in liver or kidney DNA for age-matched younger animals,128 and of the three tissues, brain adducts increased at the slowest rate of 150 adducts per cell per day, which gives the overall impression that brain DNA is more resistant to damage accumulation than many other cell types.
Cancer prevention and treatment using combination therapy with natural compounds
Published in Expert Review of Clinical Pharmacology, 2020
Chatterjee et al. showed that combined supplementation of 1α,25-dihydroxyvitamin D3 (vitD3) and fish oil induced a significant reduction in incidence, multiplicity and volume of mammary tumors in a defined experimental rat mammary carcinogenesis model [119]. They also found that the combination reduced DMBA induced mammary 7-methylguanine DNA adduct formation, retarded cell proliferation and downregulated inducible nitric oxide synthase mRNA expression compared to treatment with only one agent. Istfan et al. investigated whether vitamin D and n-3FA were capable of inhibiting cancer initiation and progression [135]. Unlike fish oil, cod liver oil has substantive concentrations of vitD. Dyck et al. reviewed the anticancer effects of vitD and n-3FA (via cod liver oil) and hypothesize that the two may work synergistically [144].
Metabonomic and transcriptomic analyses of Tripterygium glycosides tablet-induced hepatotoxicity in rats
Published in Drug and Chemical Toxicology, 2023
Zhuoling An, Yuan Sun, Chen Shi, Lihong Liu
Thirteen potential biomarkers were identified from metabonomic analysis of serum from liver-injured rats. Macrophage activation is considered to be one of the characteristics of chronic liver disease. Picolinic acid, a macrophage secondary signal related to the activation of interferon-γ, primes macrophages and triggers cytokine-driven inflammatory reactions. Elevated picolinic acid assessed in patients with chronic hepatitis C has the opposite effect in rats with DILI (Zuwała-Jagiello et al.2012). Increased L-histidinol levels have been found in long-term environmental exposure to cadmium (Gao et al.2014). As a common subordinate metabolite of fatty acids, urinary vinylacetylglycine is statistically increased in acrylamide-treated rats (Shi et al.2017). In this study, the increased vinylacetylglycine level in the TGT-induced liver injury group indicated that fatty acid metabolism might be affected and disturbed. Glutamic acid is considered to be involved in multiple biological and pathological functions in peripheral tissues, including the lung, kidney, liver, heart, stomach, and immune system (Du et al.2016). Glutamic acid participates in D-glutamine and D-glutamate metabolism, and alanine, aspartate, and glutamate metabolism. Gentisic acid is an active metabolite of salicylic acid degradation and efficiently scavenges hydroxyl radicals. The up-regulation of serum gentisic acid confirmed the occurrence of liver damage in our study. The metabolite 7-methylguanine is a product of DNA methylation and is correlative with DNA damage. The formation of 7-methylguanine was demonstrated in the liver of rats administered with hydrazine in a previous study (Becker et al.1981). Additionally, gentisic acid and 7-methylguanine are thought to have a clear, distinctive effect on liver and renal dysfunction induced by pesticides (Qi et al.2017). Serotonin was reported to relieve acetaminophen (APAP)-induced liver injury by promoting liver regeneration and inhibiting endoplasmic reticulum stress in hepatocytes undergoing apoptosis (Zhang et al.2015). Therefore, decreased serotonin levels might be an important indicator related to liver injury. Serotonin is also an important metabolite in tryptophan metabolism. Other potential biomarkers identified in the serum of rats were LPCs. Decreased levels of LPCs represent an immune-suppressive function to prevent recovery of the damaged liver (Liu et al.2013). Similar LPC trends were also observed in NAFLD, cirrhosis, valproate sodium-induced hepatotoxicity, and D-galactosamine-induced liver injury (Huo et al.2014).
Effect of lemon grass extract against methyl methanesulfonate-induced toxicity
Published in Toxin Reviews, 2021
Muqtada Ali Khan, Smita Jyoti, Falaq Naz, Gulshan Ara, Mohammad Afzal, Yasir Hasan Siddique
Out of the various chemicals that incur DNA damage, methyl methanesulfonate (MMS) records a long history of its usage as a DNA alkylating agent to induce mutagenesis and in recombination experiments (Lundin et al.2005). In the absence of destabilizing factors like oxidizing agents, acids, alkali and excess heat, MMS behaves as a stable molecule. MMS methylates the purine bases adenine (at N3) and guanine (at N7) forming 3-methyladenine and 7-methylguanine, respectively. This action results in altered pairing properties of the modified bases leading to replication blocks (Beranek 1990). DNA damage caused by MMS and other alkylating agents is corrected via DNA alkyltransferases and Base excision repair (BER) pathways. The sensitivity of cells to MMS increases significantly upon decrease in the efficiency of DNA repair mechanisms (Lundin et al.2005). Originally, methylation by MMS is known to directly induce double-strand breaks (DSBs) as the homologous recombination (HR) deficient cells are prone to MMS (Lundin et al.2005). MMS is used as a catalyst for chemical synthesis in laboratories and therefore it is believed that the exposure to MMS is limited only to laboratory personnel (HSDB 2000). As a result, no standardized exposure limit to MMS in workplace air has been proposed by the American conference of Governmental Industrial Hygienists (ACGIH 1997) and there are no existing international guidelines regarding contamination of MMS in drinking water as well (WHO 1993). MMS is known to manifest cytotoxicity via its ability to increase membrane permeability (Schwartz 1989). There is substantial toxicological data available on MMS-induced toxicity in various experimental models such as Fish, Drosophila, Chinese Hamster Ovary (CHO) cells, cultured human peripheral blood lymphocytes and rats (Solomon and Faustman 1987, Calléja et al.1999, Nishikawa et al.1999, Siddique and Afzal 2004, Kumar et al. 2011, Khanam et al.2017). Besides its catalytic role in chemical synthesis, MMS is also used as a cancer chemotherapeutic agent (Glaab et al.1998). MMS is reasonably anticipated to be a super clastogen as it forms protein adducts besides forming DNA adducts by methylating the N-terminus of valine and histidine residues in proteins (IARC 1974, 1987, Merck 1989, HSDB 2000, Zhang et al.2005). In the human blood lymphocytes, MMS induces sister chromatid exchanges (Craig-Holmes and Shaw 1977, Lambert et al.1984, Siddique and Afzal 2004). MMS-induced somatic and sex-linked mutations have been extensively studied in D. melanogaster (Yoda et al.1982).