scholarly journals Genes and enzymes of metabolic activation of xenobiotics in chemical carcinogenesis

2003 ◽  
Vol 1 (1) ◽  
pp. 30-35
Author(s):  
Veniamin V Khudolei
Keyword(s):  
Genetic Polymorphism ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Organ Specificity ◽  
Gene Products ◽  
Initial Stage ◽  
Carcinogenic Substances ◽  
Primary Key ◽  
Microsomal Hydroxylation

In the initial stage of chemical carcinogenesis the primary key event is metabolic activation of exogenic carcinogenic substances. The main enzymes of carcinogen's biotransformation (microsomal hydroxylation, reactions of conjugation) and genes which controlling the activity of these enzymes, has been characterized. The tissue(organ)specificity of expression of gene products (isoforms of su-perfamilies of CYPs and GSTs, family of NATs) as well as genetic polymorphism of enzymes involving into the biotransformation of carcinogenic xenobiotics were demonstrated

scholarly journals Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids

2021 ◽  
Vol 12 ◽  
Author(s):  
Masami Komiya ◽  
Rikako Ishigamori ◽  
Mie Naruse ◽  
Masako Ochiai ◽  
Noriyuki Miyoshi ◽  
...  
Keyword(s):  
Safety Assessment ◽  
General Procedure ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Dna Adduct ◽  
Organ Specificity ◽  
Epithelial Tissue ◽  
Target Tissue ◽  
Middle Term

Short-/middle-term and simple prediction studies for carcinogenesis are needed for the safety assessment of chemical substances. To establish a novel genotoxicity assay with an in vivo mimicking system, we prepared murine colonic/pulmonary organoids from gpt delta mice according to the general procedure using collagenase/dispase and cultured them in a 3D environment. When the organoids were exposed to foodborne carcinogens—2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) and acrylamide (AA)—in the presence of metabolic activation systems, mutation frequencies (MFs) occurring in the gpt gene dose-dependently increased. Moreover, the mutation spectrum analysis indicated predominant G:C to T:A transversion with PhIP, and A:T to C:G and A:T to T:A transversion with AA. These data correspond to those of a previous study describing in vivo mutagenicity in gpt delta mice. However, organoids derived from the liver, a non-target tissue of PhIP-carcinogenesis, also demonstrated genotoxicity with a potency comparable to colonic organoids. Organoids and PhIP were directly incubated in the presence of metabolic activation systems; therefore, there was a lack of organ specificity, as observed in vivo. Additionally, PhIP-DNA adduct levels were comparable in hepatic and colonic organoids after PhIP exposure. Taken together, the organoids prepared in the present study may be helpful to predict chemical carcinogenesis.

scholarly journals Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

2009 ◽  
Vol 60 (2) ◽  
pp. 217-242 ◽  
Author(s):  
Nada Božina ◽  
Vlasta Bradamante ◽  
Mila Lovrić
Keyword(s):  
Genetic Polymorphism ◽  
Cancer Risk ◽  
Drug Response ◽  
Cancer Susceptibility ◽  
Current Knowledge ◽  
Metabolic Activation ◽  
Metabolic Enzymes ◽  
Carcinogen Metabolism ◽  
Susceptibility Factor ◽  
Enzyme Superfamily

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer RiskThe polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping forCYPpolymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

Mediation of organ specificity in chemical carcinogenesis

1985 ◽  
Vol 16 (4) ◽  
pp. 403-407
Author(s):  
M.W. Kahng ◽  
S. Lakshmanan
Keyword(s):  
Chemical Carcinogenesis ◽  
Organ Specificity

Genetic polymorphism and variability of chemical carcinogenesis

2008 ◽  
Vol 73 (5) ◽  
pp. 543-554 ◽  
Author(s):  
G. A. Belitsky ◽  
M. G. Yakubovskaya
Keyword(s):  
Genetic Polymorphism ◽  
Chemical Carcinogenesis

THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY

2005 ◽  
Vol 45 (1) ◽  
pp. 177-202 ◽  
Author(s):  
B. Kevin Park ◽  
Neil R. Kitteringham ◽  
James L. Maggs ◽  
Munir Pirmohamed ◽  
Dominic P. Williams
Keyword(s):  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Normal Liver ◽  
Covalent Modification ◽  
Reactive Metabolites ◽  
Drug Induced ◽  
Metabolite Formation ◽  
Toxic Species ◽  
Technological Developments ◽  
Hepatic Proteins

The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.

Natural immunity to evolutionary atavistic endotoxin in carcinogenesis induced by chemical agents (a hypothesis)

2012 ◽  
Vol 19 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Elena MONCEVIČIŪTĖ-ERINGIENĖ
Keyword(s):  
Chemical Carcinogenesis ◽  
Alcaligenes Faecalis ◽  
Diagnostic Methods ◽  
Natural Immunity ◽  
Adult Rats ◽  
Age Related ◽  
Evolutionary Response ◽  
Biological Laws ◽  
Carcinogenic Substances ◽  
Stimulation Of

A hypothesis of the possibility of natural immunity to evolutionary atavistic endotoxin in chemical carcinogenesis is proposed. Age-dependent stimulation of IgM class natural specific antibodies to the endotoxin of gram-negative bacteria Alcaligenes faecalis 415 (IgMNAE) was confirmed in the blood of normal adult rats. This phenomenon was also revealed in human population. Simultaneously, the suppression and subsequent stimulation of natural immunity to endotoxin under the effect of carcinogenic substances such as benzo(a)pyrene (BP) and metylcholanthrene (MCh) were determined in rats. At first, the primary age-related and the secondary carcinogen-induced enhancement of IgMNAE was explained as the compensatory reactions of the organism’s immune system. Later on, within the evolutionary resistance theo­ry of the origin of cancer, based on the general biological laws (resistance to damage and atavism), which was formulated by the author in 2002–2005, another immunological IgMNAE enhancement mechanism was elucidated and explained by the possible activation of the dormant lipopolysaccharide mole­cules (atavistic endotoxin) alongside evolutionary resistance-related genes and oncogenes according to the inherited programme. All these mechanisms are transmitted from bacteria to mammal cells and possibly have an immense power to drive and control the process of carcinogenesis. It is the activation of these genes and their functions that helps the newly formed tumorous cells to revive the parasitic features in their unlimited division, invasiveness and metastatic growth. Its essence is a specific evolutionary response intended for the survival of damaged cells. Therefore, at present, there is a new oncological strategy problem – production of endotoxin-based vaccines and their application in cancer prophylaxis. IgMNAE can be undoubtedly helpful in elaborating new immunotherapeutic and diagnostic methods.

GUIDELINES FOR PRODUCTION OF FOOD ADDITIVES AND OTHER CHEMICAL COMMODITIES WITH LEAST CARCINOGENIC POTENTIAL: A BIOCHEMICAL APPROACH1

1971 ◽  
Vol 34 (8) ◽  
pp. 394-409
Author(s):  
Gerald M. Lower ◽  
George T. Bryan
Keyword(s):  
Parent Compound ◽  
Food Additives ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Chemical Carcinogens ◽  
Carcinogenic Activity ◽  
Carcinogenic Potential ◽  
General Chemical ◽  
Biochemical Approach ◽  
Safety Guidelines

An attempt has been made, using a biochemical approach, to construct safety guidelines for synthesis and production of food additives and other chemical commodities with “least carcinogenic potential.” In general, chemical carcinogens exist as or are metabolically activated to reactive forms able to interact with biologically-important macromolecules, a process apparently directly related to carcinogenesis by chemicals. A working knowledge of the biochemistry of biologically-foreign compounds is therefore necessary to understand structure-activity relationships observed in chemical carcinogenesis, since it appears that carcinogenic activity can be a consequence of the structure of the chemically-reactive forms of a carcinogen rather than of the structure of the parent compound. Consequently, the biochemistry of foreign compounds, the metabolic activation of various chemical carcinogens, and the nature of the probable active forms of these carcinogens has been briefly reviewed. Utilization of this knowledge by investigators of chemical carcinogenesis has proved rather helpful in the discovery of new chemical carcinogens. By eliminating from consideration those chemical with carcinogenic potential, there is no reason why this knowledge cannot be successfully utilized as an aid in the discovery of non-carcinogenic chemicals suitable for use as food additives or other chemical commodities.

Sign in / Sign up

Export Citation Format

Share Document