The Gerhard Zbinden memorial lecture: Application of biochemical and genetic approaches to understanding pathways of chemical toxicity
Section snippets
Background
Evolution has been dependent on an organism's capacity to withstand the toxic challenges which exist within its living environment. Such stresses are generated from the physical and chemical environment, e.g. from exposure to UV light, heat, molecular oxygen and heavy metals, or from exposure to chemicals produced by other organisms as part of their predatory or natural defence systems (Ames et al., 1990). The importance of these defence systems is exemplified by the large number of genes, for
Biochemical and genetic approaches in toxicology
Over 100 years ago it was demonstrated that ingested foreign chemicals are metabolised to products which can be eliminated from the body. In the mid 20th century it was shown that a wide range of metabolic pathways exist, which were classified by R.T. Williams into Phase I and Phase II reactions (Williams, 1959).
Phase I reactions are predominantly involved in the functionalisation of lipophilic chemicals, which are then further modified by conjugation with glucuronic acid, sulphate or
Application of genetics to the study of drug metabolising enzymes
In the early 1980s a number of groups, including our own, were involved in the cloning of human cytochrome P450 cDNAs. We isolated a number of cDNA clones including CYP2A6, CYP2B6 and CYP2C9. The capacity to clone and express these enzymes in a variety of recipient cells provided a powerful tool to study P450 genetics, multiplicity, regulation and substrate specificity.
To illustrate the power of this genetic approach, we showed by genetic linkage that the CYP2A and CYP2B gene loci were closely
Regulation of cytoprotective genes
Increased cellular protection in response to toxic insult can be notionally subdivided into two types of response. The first can be viewed as being adaptive and preventative, i.e. following chemical exposure the chemical is sensed, resulting in alterations in cellular functions which prevent any serious toxic effect. The second could be viewed as an acute response to life threatening stress, stress response, where normal homeostasis is lost and cellular function is profoundly altered to allow
Genetic approaches to understanding gene function and pathways of chemical toxicity
In the above discussion, a number of biochemical and genetic approaches to elucidate the role of specific genes or gene families in toxicological response have been presented, e.g. the heterologous expression of recombinant enzymes in E. coli. The complexity of adaptive response to stress, the large number of genes involved and the knowledge that chemicals may be toxic by a number of mechanisms makes the elucidation of a single gene in a pathway of toxicity extremely difficult. However,
Interface between adaptive and stress response pathways
The above data lends credence to the hypothesis that individual proteins involved in cytoprotection have evolved multiple functions both in adaptive and in stress response pathways. This may allow us to rationalise apparently contradictory findings on the role of these proteins in cytoprotection as is the case with p53, stress signalling and now also detoxification enzymes. There are a number of clues, which identify the capacity to resist oxidative stress as a key common modulator in many of
Acknowledgments
I should like to pay particular thanks to Dr Lawrie King, Dr Dick Philpot, Dr Franz Oesch and Dr Nick Hastie who have all played an important part in the development of the research discussed above, both practically and intellectually. I should also like to thank my collaborators for their the invaluable contributions, particularly Professor John Hayes, Dr Richard Meehan, Dr John Miles, Dr. Lesley Forrester and Dr. Colin Henderson, and Janis Sweeney and Margaret Rooney for their loyal and
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Disruption of the glutathione transferase Pi class genes
2005, Methods in EnzymologyCitation Excerpt :Although GSTs are ubiquitously expressed, tissue distribution can vary widely between species; there is also a difference between fetal expression and that found in the adult. Furthermore, GST may be induced by a wide range of structurally unrelated compounds, some of which may be substrates, giving credence to the view that GST are part of an adaptive response to cellular stress (Hayes and McLellan, 1999; Hayes et al., 2005; Townsend and Tew, 2003; Wolf, 2002). Overall, expression and regulation of GST is complex and highly species‐dependent; additional complexities arise from the findings that many of the GST isoforms are polymorphic in man (see later).
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EUROTOX has instituted this lecture to honour the memory of Gerhard Zbinden (1924–1993), EUROTOX honorary Member and recipient of the EUROTOX Merit Award. The Gerhard Zbinden Memorial Lecture aims at recognising scientific excellence in the area of drug and chemical safety. The lecture is held at the Annual EUROTOX Congress by a scientist chosen for his/her outstanding research contributions to the science of toxicology.