China
Africa
Explore chapters and articles related to this topic
Adverse Effects and Intoxication with Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
However, the carcinogenic potency appears to be relatively low and dependent on the metabolism. Safrole is metabolically activated through the formation of intermediates, and these are able to directly react with DNA. Two bioactivation pathways of safrole to potentially hepatotoxic intermediates have been reported. One involves P450-catalyzed hydroxylation, thereby producing 1′-hydroxysafrole, and on further conjugation with sulfate, generating a reactive sulfate ester. This ester creates a highly reactive carbocation, which alkylates DNA. The second pathway involves P450-catalyzed hydroxylation of the methylenedioxy ring and finally formation of reactive p-quinone methide. Both pathways could explain the genotoxic effects of safrole. DNA adducts have been identified in vitro and in vivo (see Dietz and Bolton, 2005).
Measurement of Exposure and Dose
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Especially exciting opportunities for biomarkers of exposure are found in DNA adducts. The active forms of many chemical carcinogens are metabolites which bind to cellular macromolecules, including nucleic acids and proteins; the product of these bindings are called adducts. The formation of DNA adducts are thought by many to be cancer-initiating events (Wogan and Tannenbaum, 1987). What better index of the biologically effective dose than the actual dose causing the initiating event itself. As discussed earlier (Chap. 2), in addition to initiation, the progression step in carcinogenesis may also require a DNA-damaging event. Thus, DNA adducts may be indicators of exposure affecting both early and late steps in cancer development (Harris, 1985). Much work has been done to build an understanding of the relationship between exposure or, in experimental animals, administered dose, and the levels of DNA adducts. A linear relationship is often, but not always, found (Perera, 1987; Belinsky et al., 1987; Adriaenssens et al., 1983; Dunn, 1983). Pharmacokinetics, discussed in a later chapter, rules this relationship.
Perception, Planning, and Scoping, Problem Formulation, and Hazard Identification
Published in Ted W. Simon, Environmental Risk Assessment, 2019
A number of endogenous and exogenous chemical react with DNA to form adducts. The use of DNA adducts as biomarkers of exposure is problematic because a huge amount of DNA damage occurs due to endogenous substances and oxidative stress.88,89 Endogenous DNA damage is often indistinguishable from that due to chemical exposure, and this greatly complicates the assessment of DNA adducts as biomarkers of exposure. The mere presence of adducts cannot be indicative of a potential deleterious effect of a chemical.
Protective Effects of Pelargonidin against DMBA-Induced Mammary Tumorigenesis in BALB/c Mice through Reduced Oxidative Stress and Lipid Anomalies
Published in Nutrition and Cancer, 2023
Yahyea Baktiar Laskar, Kasturi Bhattacharjee, Moumita Nath, Yashmin Choudhury, Pranab Behari Mazumder, Anupam Das Talukdar
In the present study, the therapeutic potential of pelargonidin was investigated in a chemical-induced murine breast cancer model, and the results were compared with a commonly prescribed SERM drug, tamoxifen. The study also emphasized reaching a plausible mechanism of anti-tumoral activity of pelargonidin against DMBA-induced mammary carcinogenesis. The polycyclic aromatic hydrocarbons (PAH), 7, 12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer is recognized as the earliest ER-positive mouse model, introduced by Medina et al. (51). In addition, Alvardo et al. (52) demonstrated that DMBA-induced mammary carcinomas were positive for both ER and progesterone receptor (PR), with a higher expression of ERα when compared to PR. In the present study, DMBA effectively induced tumorigeneses in the mammary fat-pad of BALB/c mice. Besides, damage to liver tissues was also observed in DMBA-exposed mice, probably due to oral administration of DMBA that was transported via the gastrointestinal tract. The DMBA-induced carcinogenesis initiates mainly by generating free radicals (epoxide) that can bind to DNA, forming DNA adducts. These DNA adducts are capable of promoting mutations that lead to tumor development. In particular, DMBA-induced rodent mammary carcinogenesis is also attributed to the estradiol-mimicking potential of DMBA that help it to bind estradiol receptor (ER) and helps enhance the ER-mediated growth signaling (53).
Modulatory effect of myricitrin against chromosome instability and cytostasis induced by bleomycin and oxaliplatin in CHO-K1 cells
Published in Drug and Chemical Toxicology, 2023
Ana Paula de Souza, Raíne Fogliati Schardosim, Juliana Escouto Al Kateeb, Mauricio Lehmann, Ivana Grivicich, Rafael Rodrigues Dihl
The assessment of MYR against chromosomal instability induced by OXL indicated an increase in the frequencies of MNi and NPBs, in the post-treatment protocol, at all concentrations tested, when compared to the results obtained from the action of OXL alone. This result revealed that MYR was able to potentiate OXL-induced lesions. OXL causes DNA damage through the formation of inter- and intra-chain adducts in the DNA molecule (Ganaie et al. 2019, Rottenberg et al. 2021). The adducts interfere with essential cellular processes, such as cell cycle and DNA repair mechanisms (Howells et al. 2007, Rottenberg et al. 2021). In mammalian cells, nucleotide excision repair (NER) is the main DNA repair mechanism to remove bulky (helix distorting) lesions, nucleotide deletion being part of this process (Lee and Kang 2019). Thus, NER is impaired due to the binding of OXL to DNA, resulting in genomic lesions that give rise to chromosomal aberrations and fragmentation, sister chromatid breaks and translocations, hence increasing the frequency of MNi, NPBs and NBUDs (Povirk 1996, Jagetia et al. 2007, Danesi et al. 2012, Brandt and Gerrietes 2020).
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
APAP-protein adduct formation is specific for proteins in liver. Adduct formation occurs before toxicity and a number of specific proteins are primary targets. Figure 4 is an immunoblot of the liver cytosolic fraction from a mouse 2 h after a hepatotoxic dose of APAP, taken from the first study to identify a specific target of APAP binding (Cohen and Khairallah 1997). Note a major protein adduct at approximately 58 kDa. This protein was isolated and identified as the selenium binding protein (Pumford et al. 1992; Hoivik et al. 1996), which had been previously shown to associate with selenium following a tracer dose of the metal. A large number of other proteins have been subsequently identified, but the relevance of APAP binding of the selenium binding protein or any other protein relative to toxicity has never been defined (James, Mayeux, et al. 2003).