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Nature and nurture – lessons from chemical carcinogenesis

Key Points

  • Associations between cancer and occupational exposures can be dated back into the sixteenth century.

  • Today, about 200 different chemical compounds and mixtures are known or anticipated to be human carcinogens.

  • The great majority of human chemical carcinogens require metabolic activation to elicit detrimental effects. The activity of 'xenobiotic metabolizing enzymes' such as cytochrome-P450-dependent monooxygenases, glutathione S-transferases, sulphotransferases and others are required for activation (toxication) of important carcinogens.

  • Human carcinogens act through a variety of genotoxic and non-genotoxic mechanisms. DNA binding and induction of mutations in cancer-susceptibility genes, such as TP53 and KRAS, are import mechanisms of tumour initiation. In addition, the accompanying ability of many compounds to promote the outgrowth of transformed cell clones has been acknowledged.

  • The preferential formation of certain stereoisomers during metabolic activation of genotoxic carcinogens can determine the level of DNA damage, the efficiency of DNA repair, and the carcinogenic potency of a compound.

  • Humans are exposed to mixtures of compounds with different degrees of biological activity. Analysis of compound-specific mutational patterns provides valuable clues on the contribution of individual chemicals (or single classes of chemicals) to the overall biological response to these mixtures observed in certain tissues.


The roles of genetic constitution versus environmental factors in cancer development have been a matter of debate even long before the discovery of 'oncogenes'. Evidence from epidemiological, occupational and migration studies has consistently pointed to environmental factors as the major contributing factors to cancer, so it seems reasonable to discuss the importance of chemical carcinogenesis in the present 'age of cancer genetics'.

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Figure 1: Sir Ernest Laurence Kennaway (1881–1958) and his co-workers.
Figure 2: Enzymatic conversion of some selected human carcinogens towards their ultimate DNA-reactive metabolites.
Figure 3: Overview of genotoxic and non-genotoxic effects of carcinogens.
Figure 4: Tumour promotion and tumour initiation.


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I am very grateful to my colleague and friend G. P. Tochtrop for his critical reading of the manuscript. I also want to acknowledge the help and kind advice from J. Eckert in the 'Rare Books and Special Collections' department of the Francis A. Countway Library of Medicine, Harvard Medical School, Boston, Massachusetts. I wish to thank the staff of the Houghton Library, Harvard University, Cambridge, Massachusetts, for their help with Paracelsus' books. The work of the author was supported by the German Research Foundation.

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Having an affinity for negative charge; molecules that behave as electron acceptors.


Having an affinity for positive charge; molecules that behave as electron donors.


Hydrocarbons containing a carbon–carbon double bond; also known as alkenes.


Vesicles formed from the endoplasmatic reticulum when cells are disrupted; used in cell-free in vitro studies of biotransformation.


Enzymes that catalyse oxidation–reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. Also known as monooxygenases or hydroxylases.


Haem-containing protein involved in electron-transfer reactions.


Chemical compounds that are foreign to the biological system.


Enzymatically catalysed chemical alterations of a compound that occur within living organisms or cells.


Saturated hydrocarbons containing two halogen atoms (for example, chlorine) that are bonded to adjacent carbon atoms.


Molecules that have two-dimensional structures.


A chemical reaction in which an oxygen is joined to an olefinic molecule to form a cyclic, three-membered ether. The products are known as oxiranes, epoxides or simply oxides.


Chemical carcinogens that are capable of causing damage to DNA. These can be mutagenic, clastogenic or aneugenic.


Covalent reaction products between chemicals and proteins or DNA.


Stereoisomers that are not related as mirror images to each other.


One of the two non-superimposable mirror image forms of an optically active molecule.

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Luch, A. Nature and nurture – lessons from chemical carcinogenesis. Nat Rev Cancer 5, 113–125 (2005).

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