- Email: [email protected]
Glutathione conjugation; mechanisms and biological significance
293
Measuring and minimizing disturbance tu rodents Disturbance Index Method for Assessing Severity of Procedures on Rodents
pad injection and administration of substances by mouth) and mice (to assess effects of duration of restraint, unskilled handling, diameter of hypodermic needles, route and volume of injections and macrophage-inducing agents).
The resulb obtained suggest that
This is a very encouraging development. Nevertheless, determining the DI properly will require experience, as well as the necessary equipmertt. Thus, it might be preferable for one or two groups to work out the best way of carrying out commonly used procedures, and to provide a service with regard to novel procedures, rather than adding experiments on rodent behaviour to the repertoire of licensees in general!
the DI method could be used to work out the least disturbing way of performing a particular pro-
i3XiI.i~.
&he Animals (Scientific Procedures) Act 2986 requires the UK Home Office to weigh the likely adverse effects OR animals against the benefits likely to accrue before a project licence for a particular programme of work is granted; personal licence holders are required to take precautions to minimize any pain, distress or discomfort caused to itnimafs used on their own licensed project work. These statutory requirements, which assume that animal suffering is not only recognizable, but measurable, have led a number of experienced individuals and animal welfare organizations to begin to devise schemes for making the necessary assessments. This report describes work, begun at the University of Dundee and funded by the Universities Federation for ArGmal Welfare, which involves assessing the degree af disturbance to a rodent’s exploratory behaviour caused by subjecting it to an experimental procedure. A disturbance index (DI) is produced, which can be statistically compared with a control value and with Dis generated by using sedative and stirn~~a~~ substances. This navel approach depends on the fact that, faced with a new environment, rats and mice tend to explore in a very similar manner, i.e. by making a number of movements whish can be measured electronically by an activity monitor. The DI method was applied to rats (to assess effects of drugs, forms of manual restraint, volumes of intraperitoneal injection, foot
Minirrrking disturbance to rodents
Not just anutha$ detoxification pathway Glutathione Conjugation: Mechanisms and Biological Significance edited by Hefmut Sies and Brian Acade~j~ Press, 2988. f47.SOIUS$95.00 (480 pages) 1SBN 0 12 642755 0 Letterer,
In the relatively long scientific history of glutathic2e conjugation, which started in 1879 when the first mercapturates were isolated from dogs dosed with bromobenzene by Baumann, Preusse and Jaff& the interest in this field has varied widely. The last few years, however, have witnessed an unprecedented increase in the atten-
tion directed towards this bio~an~fo~a~on pathway. A reaction which was seen as ‘just one of the detoxification pathways’ for xenobiotics was shown firstly to form toxicologically important derivatives and then to participate in the formation of the Ieukotrienes, a ciass of important chemical mediator arising from arachidonic acid. On the heels of this development for the conjugates followed several advances in enzymology: the finding of increased expression of certain classes of glu~~ione S-transferase in tumor cefls, making these emymes potentially valuable tumor markers; and the recognition of the role played by increased expression of the transferases in the mechanism by which
TiPS -July 1989 [Vol. 101
294 certain tumor cells become resistan’ to rytostatic drugs. This latter has made the inhibition of the enzymes a new target for drug development. The growing interest in the glutatione S-transferases and the reactions they catalyse has been reflected in the number of excellent reviews on the subject published in the last few years. However, a need clearly existed for a comprehensive book combining both the basic and the newer aspects of the chemistry, biochemistry, molecular biology and toxicology related to glutathione conjugation, and the editors of this book have succeeded in getting together a number of the leading investigators in all these areas. The first two chapters are devoted to the chemistry of glutathione conjugation. A very comprehensive review (by K. T. Douglas) of the reactions of glutathione as a nucleophile, with all imaginable reactants, in relation to the mechanism of the enzyme is followed by a chapter dealing with free radical reactions and describing recent insights into conjugation reactions (mainly with oxygen and glutathione itself) of thiyl radicals. The next part of the book deals with enzymes. The soluble glutathione S-transferases of rat, mouse, humans and numerous other creatures are treated in depth by B. Ketterer. C. B. Pickett details the structure and regulation of mammalian transferases at the gene level. Lastly, the membranebound transferases are summarized by R. Morgenstem. The transport of conjugates is then discussed by H. Sies, but only in the last few chapters is the further metabolism of glutathione conjugates treated: G. J. Mulder describes his efforts to find a suitable substrate to monitor in-uivo glutathione S-transferase activity; L. F. Chasseaud gives an excellent overview of the possibilities and limitations of thioether (i.e. mercapturate) excretion as an index of exposure to electrophilic agents in the workplace and its potential use in animal expefiments; and W. DeKant describes the formation of reactive thiols through the action of fi-lyase on the cysteine conjugates. A readable chapter on leukotienes by M. Huber is also tucked away at the end of the book.
aspect
The middle portion of the book is formed by chapters on various toxicological aspects: L. A. Peterson and ti. P. Guengerich very nicely treat the interrelationship between cytochrome P-450 and the glutathione S-transferases using several important industrial chemicals as examples. The detoxification of various carcinogens is then described by J. Hinson and F. F. Kadlubar. The chapter by G. A. Neal takes us from carcinogen metabolism to the role of the transferases in tumor cells and thus forms the transition to the chapter by J. D. Hayes and C. R. Wolfe, who provide an in-depth discussion of the hottest topic of the day, the role of overexpression of the glutathione S-transferases in the development of resistance of
cells toward cytostatic compounds. Interestingly they take the issue one step further and also treat resistance to herbicides and inwhich presumably secticides, occur by similar mechanisms. Although this book is written at a level suitable for people with research interests in the field, for whom it will stay a reference work of importance for some time, it should also prove useful as a ‘starter’ for people when they first become interested in the various aspects of glutathione conjugation.
Manual of drug development
drugs. The emphasis, probably because of- the author’s background, is on research and development and a cursory glance through the book reveals little of interest to the modem pharmacologist. Rather, the book appears to be more of a management manual. I found, however, that on closer scrutiny it was eminently readable, nicely produced and well thought out, with a logical ordering of the sections. It concentrates on the overall picture with sections on drug discovery and development, corporate organization and management issues, research and development organization and management issues, technical and function issues and external interactions and relationships. The book is not written as a panacea; the author attempts to provide a balanced view of the ways in which the drug industry in general operates. Usually more than one alternative is presented. The author very rarely offers criticism or advice, but generally presents the alternatives and leaves the reader to his or her own conclusions. Only on the subject of the new technology does the author reveal his bias. Here he refers to ‘media hype’, ‘proteins looking fur a disease’, and to ‘molecular modelling even if able to pro-
Multinational Drug Companies: Issues in Drug Discovery and Development
by Bert Spilker, Raven Press, 2988. $86.50 (xxvi + 602 pages) ISBN 0 88167 463 X The author of this book is a physi-
cian and pharmacologist who is currently Department Head of Project Coordination at Burroughs Wellcome Company USA. He has a wide experience with several major drug companies in the United States and Europe. He is thus well qualified to write the book, which is over 600 pages long, and which attempts to provide a background thesis on the pharmaceutical industry from the first steps of discovery to the marketing of a new drug. Some pharmacologists might disagree with the author’s assertion on p. 78 that a chemical compound should first be referred to as a drug when it is initially given to humans. They may prefer the well known definition that a drug is ‘a substance which when injected into experimental animals results in the publi-
cation of a scientific paper’. The book is written mainly for
the senior and junior executives in pharmaceutical companies who have little formal scientific training, and also for scientists and clinicians directly involved in the discovery and development of
PETER J. VAN
BLADEREN
Department of Biological Toxicology, TNOClVO Toxicology and Nutrition Institute, PO Box 360.3700 AJ i&t, Netherlands.
duce accurate predictions not generating positive results in humans‘. Although some will agree with this philosophy there is much speculative development in this area and many major drug companies have
Measuring and minimizing disturbance tu rodents Disturbance Index Method for Assessing Severity of Procedures on Rodents
pad injection and administration of substances by mouth) and mice (to assess effects of duration of restraint, unskilled handling, diameter of hypodermic needles, route and volume of injections and macrophage-inducing agents).
The resulb obtained suggest that
This is a very encouraging development. Nevertheless, determining the DI properly will require experience, as well as the necessary equipmertt. Thus, it might be preferable for one or two groups to work out the best way of carrying out commonly used procedures, and to provide a service with regard to novel procedures, rather than adding experiments on rodent behaviour to the repertoire of licensees in general!
the DI method could be used to work out the least disturbing way of performing a particular pro-
i3XiI.i~.
&he Animals (Scientific Procedures) Act 2986 requires the UK Home Office to weigh the likely adverse effects OR animals against the benefits likely to accrue before a project licence for a particular programme of work is granted; personal licence holders are required to take precautions to minimize any pain, distress or discomfort caused to itnimafs used on their own licensed project work. These statutory requirements, which assume that animal suffering is not only recognizable, but measurable, have led a number of experienced individuals and animal welfare organizations to begin to devise schemes for making the necessary assessments. This report describes work, begun at the University of Dundee and funded by the Universities Federation for ArGmal Welfare, which involves assessing the degree af disturbance to a rodent’s exploratory behaviour caused by subjecting it to an experimental procedure. A disturbance index (DI) is produced, which can be statistically compared with a control value and with Dis generated by using sedative and stirn~~a~~ substances. This navel approach depends on the fact that, faced with a new environment, rats and mice tend to explore in a very similar manner, i.e. by making a number of movements whish can be measured electronically by an activity monitor. The DI method was applied to rats (to assess effects of drugs, forms of manual restraint, volumes of intraperitoneal injection, foot
Minirrrking disturbance to rodents
Not just anutha$ detoxification pathway Glutathione Conjugation: Mechanisms and Biological Significance edited by Hefmut Sies and Brian Acade~j~ Press, 2988. f47.SOIUS$95.00 (480 pages) 1SBN 0 12 642755 0 Letterer,
In the relatively long scientific history of glutathic2e conjugation, which started in 1879 when the first mercapturates were isolated from dogs dosed with bromobenzene by Baumann, Preusse and Jaff& the interest in this field has varied widely. The last few years, however, have witnessed an unprecedented increase in the atten-
tion directed towards this bio~an~fo~a~on pathway. A reaction which was seen as ‘just one of the detoxification pathways’ for xenobiotics was shown firstly to form toxicologically important derivatives and then to participate in the formation of the Ieukotrienes, a ciass of important chemical mediator arising from arachidonic acid. On the heels of this development for the conjugates followed several advances in enzymology: the finding of increased expression of certain classes of glu~~ione S-transferase in tumor cefls, making these emymes potentially valuable tumor markers; and the recognition of the role played by increased expression of the transferases in the mechanism by which
TiPS -July 1989 [Vol. 101
294 certain tumor cells become resistan’ to rytostatic drugs. This latter has made the inhibition of the enzymes a new target for drug development. The growing interest in the glutatione S-transferases and the reactions they catalyse has been reflected in the number of excellent reviews on the subject published in the last few years. However, a need clearly existed for a comprehensive book combining both the basic and the newer aspects of the chemistry, biochemistry, molecular biology and toxicology related to glutathione conjugation, and the editors of this book have succeeded in getting together a number of the leading investigators in all these areas. The first two chapters are devoted to the chemistry of glutathione conjugation. A very comprehensive review (by K. T. Douglas) of the reactions of glutathione as a nucleophile, with all imaginable reactants, in relation to the mechanism of the enzyme is followed by a chapter dealing with free radical reactions and describing recent insights into conjugation reactions (mainly with oxygen and glutathione itself) of thiyl radicals. The next part of the book deals with enzymes. The soluble glutathione S-transferases of rat, mouse, humans and numerous other creatures are treated in depth by B. Ketterer. C. B. Pickett details the structure and regulation of mammalian transferases at the gene level. Lastly, the membranebound transferases are summarized by R. Morgenstem. The transport of conjugates is then discussed by H. Sies, but only in the last few chapters is the further metabolism of glutathione conjugates treated: G. J. Mulder describes his efforts to find a suitable substrate to monitor in-uivo glutathione S-transferase activity; L. F. Chasseaud gives an excellent overview of the possibilities and limitations of thioether (i.e. mercapturate) excretion as an index of exposure to electrophilic agents in the workplace and its potential use in animal expefiments; and W. DeKant describes the formation of reactive thiols through the action of fi-lyase on the cysteine conjugates. A readable chapter on leukotienes by M. Huber is also tucked away at the end of the book.
aspect
The middle portion of the book is formed by chapters on various toxicological aspects: L. A. Peterson and ti. P. Guengerich very nicely treat the interrelationship between cytochrome P-450 and the glutathione S-transferases using several important industrial chemicals as examples. The detoxification of various carcinogens is then described by J. Hinson and F. F. Kadlubar. The chapter by G. A. Neal takes us from carcinogen metabolism to the role of the transferases in tumor cells and thus forms the transition to the chapter by J. D. Hayes and C. R. Wolfe, who provide an in-depth discussion of the hottest topic of the day, the role of overexpression of the glutathione S-transferases in the development of resistance of
cells toward cytostatic compounds. Interestingly they take the issue one step further and also treat resistance to herbicides and inwhich presumably secticides, occur by similar mechanisms. Although this book is written at a level suitable for people with research interests in the field, for whom it will stay a reference work of importance for some time, it should also prove useful as a ‘starter’ for people when they first become interested in the various aspects of glutathione conjugation.
Manual of drug development
drugs. The emphasis, probably because of- the author’s background, is on research and development and a cursory glance through the book reveals little of interest to the modem pharmacologist. Rather, the book appears to be more of a management manual. I found, however, that on closer scrutiny it was eminently readable, nicely produced and well thought out, with a logical ordering of the sections. It concentrates on the overall picture with sections on drug discovery and development, corporate organization and management issues, research and development organization and management issues, technical and function issues and external interactions and relationships. The book is not written as a panacea; the author attempts to provide a balanced view of the ways in which the drug industry in general operates. Usually more than one alternative is presented. The author very rarely offers criticism or advice, but generally presents the alternatives and leaves the reader to his or her own conclusions. Only on the subject of the new technology does the author reveal his bias. Here he refers to ‘media hype’, ‘proteins looking fur a disease’, and to ‘molecular modelling even if able to pro-
Multinational Drug Companies: Issues in Drug Discovery and Development
by Bert Spilker, Raven Press, 2988. $86.50 (xxvi + 602 pages) ISBN 0 88167 463 X The author of this book is a physi-
cian and pharmacologist who is currently Department Head of Project Coordination at Burroughs Wellcome Company USA. He has a wide experience with several major drug companies in the United States and Europe. He is thus well qualified to write the book, which is over 600 pages long, and which attempts to provide a background thesis on the pharmaceutical industry from the first steps of discovery to the marketing of a new drug. Some pharmacologists might disagree with the author’s assertion on p. 78 that a chemical compound should first be referred to as a drug when it is initially given to humans. They may prefer the well known definition that a drug is ‘a substance which when injected into experimental animals results in the publi-
cation of a scientific paper’. The book is written mainly for
the senior and junior executives in pharmaceutical companies who have little formal scientific training, and also for scientists and clinicians directly involved in the discovery and development of
PETER J. VAN
BLADEREN
Department of Biological Toxicology, TNOClVO Toxicology and Nutrition Institute, PO Box 360.3700 AJ i&t, Netherlands.
duce accurate predictions not generating positive results in humans‘. Although some will agree with this philosophy there is much speculative development in this area and many major drug companies have