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BackgroundThe extensive use of pyrethroids for control of malaria vectors, driven by their cost, efficacy and safety, has led to widespread resistance. To favor their sustainable use, the World Health Organization (WHO) formulated an insecticide resistance management plan, which includes the identification of the mechanisms of resistance and resistance surveillance. Recognized physiological mechanisms of resistance include target site mutations in the para voltage-gated sodium channel, metabolic detoxification and penetration resistance. Such understanding of resistance mechanisms has allowed the development of resistance monitoring tools, including genotyping of the kdr mutation L1014F/S in the para gene.MethodsThe sequence-based technique RNA-seq was applied to study changes in the transcriptome of deltamethrin-resistant and -susceptible Anopheles gambiae mosquitoes from the Western Province of Kenya. The resulting gene expression profiles were compared to data in the most recent literature to derive a list of candidate resistance genes. RNA-seq data were analyzed also to identify sequence polymorphisms linked to resistance.ResultsA total of five candidate-resistance genes (AGAP04177, AGAP004572, AGAP008840, AGAP007530 and AGAP013036) were identified with altered expression between resistant and susceptible mosquitoes from West and East Africa. A change from G to C at position 36043997 of chromosome 3R resulting in A101G of the sulfotransferase gene AGAP009551 was significantly associated with the resistance phenotype (odds ratio: 5.10). The kdr L1014S mutation was detected at similar frequencies in both phenotypically resistant and susceptible mosquitoes, suggesting it is no longer fully predictive of the resistant phenotype.ConclusionsOverall, these results support the conclusion that resistance to pyrethroids is a complex and evolving phenotype, dependent on multiple gene functions including, but not limited to, metabolic detoxification. Functional convergence

Honingbijen komen bij het foerageren met allerlei stoffen in aanraking, ook met insecticiden.Maar ze zijn ook in staat tot ontgiften. Dit artikel geeft uitleg over het mechanisme daarvan enover recent onderzoek op dit gebied aan bijen.

Honingbijen komen bij het foerageren met allerlei stoffen in aanraking, ook met insecticiden. Maar ze zijn ook in staat tot ontgiften. Dit artikel geeft uitleg over het mechanisme daarvan en over recent onderzoek op dit gebied aan bijen.

Mercury is notorious for its bioaccumulation in the organisms and biomagnification along the food web. However, research on the effects of mercury to phytoplankton, at the bottom of aquatic food chain, is inadequate. Therefore, the present study investigated toxicity, detoxification, toxicity prediction and pre-exposure effects of inorganic mercury and methylmercury in marine phytoplankton. We found that: (1) MeHg had no influence on the electron transport chain, but it inhibited population growth by reducing the rate of algal cells division. In contrast, Hg(II) could inhibit the electron transport chain, reduce the cell viability and then population growth. (2) Phytoplankton could synthesize phytochelatins (PCs) to cope with mercury stress. Both synthesis and degradation/export of PCs showed rapid response to mercury exposure. And the ability of MeHg to induce PCs was much lower than that of Hg(II). (3) Both subcellular fraction and speciation of mercury could explain and predict the interspecies differences in mercury sensitivity. For MeHg, the species-related sensitivity could be interpreted by organelles, metal-rich granule (MRG), or metal sensitive fraction (MSF) based MeHg. While For Hg(II), heat-stable protein (HSP) or biologically detoxified metal (BDM) may be the best predictor of the growth inhibition. And the Hg(II) tolerance also increased with the ability of phytoplankton to biotransform Hg(II) to PCs-Hg complex and metacinnabar (β-HgS). (4) A unchanged tolerance to Hg(II) while an enhanced tolerance to MeHg were observed in the multi-generation exposed algal cells, which may be resulted from the changes in cellular mercury accumulation and their detoxification ability. Overall, our studies demonstrated the toxicity and detoxification mechanisms of Hg(II) and MeHg in marine phytoplankton, which are significant in understanding the changes in mercury trophic transfer and community composition.

cum laude graduation (with distinction)

Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2008., Page 362 blank., Includes bibliographical references., Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species., (cont.) Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occurring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemical-rich prey have evolved both general (GST and ABC transporters) and allelochemical-specific (CYP) detoxification mechanisms to tolerate prey chemical defenses., by Kristen Elizabeth Whalen., Ph.D.

Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2008., Page 362 blank., Includes bibliographical references., Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species., (cont.) Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occurring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemical-rich prey have evolved both general (GST and ABC transporters) and allelochemical-specific (CYP) detoxification mechanisms to tolerate prey chemical defenses., by Kristen Elizabeth Whalen., Ph.D.

Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2008., Page 362 blank., Includes bibliographical references., Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species., (cont.) Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occurring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemical-rich prey have evolved both general (GST and ABC transporters) and allelochemical-specific (CYP) detoxification mechanisms to tolerate prey chemical defenses., by Kristen Elizabeth Whalen., Ph.D.

Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2008., Page 362 blank., Includes bibliographical references., Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species., (cont.) Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occurring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemical-rich prey have evolved both general (GST and ABC transporters) and allelochemical-specific (CYP) detoxification mechanisms to tolerate prey chemical defenses., by Kristen Elizabeth Whalen., Ph.D.

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2008, Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification of ichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occuring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of de, Financial support for this research was provided by the following organizations and individuals: National Science Foundation Graduate Research Fellowship, Tropical Research Initiative Grant – Ocean Life Institute (WHOI), Ocean Ventures Fund (WHOI), National Undersea Research Center – Caribbean Marine Research Center, Program Development Proposal (CMRC-03-PRMN-01-03A), Seaspace Student Scholarship, Conchologists of America Student Award, NOAA National Sea Grant College Program (Grant No. NA16RG2273), Woods Hole Oceanographic Institution - Sea Grant (Project No. R/P-66), A grant from Walter A. and Hope Noyes Smith supported proteomic work at the University of California, Davis – Proteomics Center, Academic Programs Office, Woods Hole Oceanographic Institution

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2008, Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification of ichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occuring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of de, Financial support for this research was provided by the following organizations and individuals: National Science Foundation Graduate Research Fellowship, Tropical Research Initiative Grant – Ocean Life Institute (WHOI), Ocean Ventures Fund (WHOI), National Undersea Research Center – Caribbean Marine Research Center, Program Development Proposal (CMRC-03-PRMN-01-03A), Seaspace Student Scholarship, Conchologists of America Student Award, NOAA National Sea Grant College Program (Grant No. NA16RG2273), Woods Hole Oceanographic Institution - Sea Grant (Project No. R/P-66), A grant from Walter A. and Hope Noyes Smith supported proteomic work at the University of California, Davis – Proteomics Center, Academic Programs Office, Woods Hole Oceanographic Institution

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2008, Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification of ichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occuring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of de, Financial support for this research was provided by the following organizations and individuals: National Science Foundation Graduate Research Fellowship, Tropical Research Initiative Grant – Ocean Life Institute (WHOI), Ocean Ventures Fund (WHOI), National Undersea Research Center – Caribbean Marine Research Center, Program Development Proposal (CMRC-03-PRMN-01-03A), Seaspace Student Scholarship, Conchologists of America Student Award, NOAA National Sea Grant College Program (Grant No. NA16RG2273), Woods Hole Oceanographic Institution - Sea Grant (Project No. R/P-66), A grant from Walter A. and Hope Noyes Smith supported proteomic work at the University of California, Davis – Proteomics Center, Academic Programs Office, Woods Hole Oceanographic Institution

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2008, Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification of ichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occuring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of de, Financial support for this research was provided by the following organizations and individuals: National Science Foundation Graduate Research Fellowship, Tropical Research Initiative Grant – Ocean Life Institute (WHOI), Ocean Ventures Fund (WHOI), National Undersea Research Center – Caribbean Marine Research Center, Program Development Proposal (CMRC-03-PRMN-01-03A), Seaspace Student Scholarship, Conchologists of America Student Award, NOAA National Sea Grant College Program (Grant No. NA16RG2273), Woods Hole Oceanographic Institution - Sea Grant (Project No. R/P-66), A grant from Walter A. and Hope Noyes Smith supported proteomic work at the University of California, Davis – Proteomics Center, Academic Programs Office, Woods Hole Oceanographic Institution

During and after absorption in the intestine, quercetin is extensively metabolised by the phase II biotransformation system. Because the biological activity of flavonoids is dependent on the number and position of free hydroxyl groups, a first objective of this thesis was to investigate the consequences of phase II metabolism of quercetin for its biological activity. For this purpose, a set of analysis methods comprising HPLC-DAD, LC-MS and 1 H NMR proved to be a useful tool in the identification of the phase II metabolite pattern of quercetin in various biological systems. These studies showed that the 3'- and 4'-hydroxyl groups of quercetin, (catechol hydroxyl groups) were important targets for methylation, sulfation and glucuronidation. Methylation of a catechol hydroxyl group of quercetin proved to decrease the pH-dependent radical scavenging capacity of the compound, both by increasing its pK a for deprotonation and by decreasing its electron-donating properties. Methylation of a catechol hydroxyl group had a similar effect as replacement of the hydroxyl group by a hydrogen atom. Regarding the pro-oxidant properties of quercetin, methylation of a catechol hydroxyl group of quercetin did not eliminate the pro-oxidant chemistry of quercetin, reflected in the formation of covalent adducts with glutathione upon oxidation of quercetin by horseradish peroxidase. However, methylated quercetin proved to form only 42% of the level of DNA adducts in exposed cells as compared to a similar amount of unconjugated quercetin, indicating that methylation of quercetin attenuates also this biological reactivity towards DNA.A second objective of this thesis was to obtain more insight into the possible toxic effects of quercetin by studying various mechanisms that might be relevant in the context of carcinogenesis. Quercetin appeared to have a biphasic effect on the proliferation of cancer cell lines expressing the estrogen receptor (ER). The stimulation of cancer cell proliferati

The glutathione S-transferases (GST) are a family of isoenzymes serving a major part in the biotransformation of many reactive compounds. The isoenzymes from rat, man and mouse are divided into three classes, alpha, mu and pi, on the basis of similar structural and enzymatic properties.The main function of the glutathione S-transferases isthe catalysisof the conjugation of electrophilic, hydrophobic compounds with the tripeptide glutathione (GSH). In addition, some of the isoenzymes are capable of binding a number of non-substrate ligands non-covalently. The reaction with GSH generally results in the formation of less toxic compounds, however, several cases of activation are also known.Since the individual isoenzymes demonstrate differential though overlapping substrate selectivities, the actual isoenzyme pattern determines the extent to which detoxification and/or activation occurs. Consequently, an individual's susceptibility towards electrophilic compounds is not only dependent on substrate specificity, but also on factors determining the isoenzyme profile of the glutathione S-transferases, including generic factors as well as external factors causing changes in the levels or activities of individual isoenzymes.The studies in this thesis were aimed at the relationship: glutathione S-transferase isoenzyme patterns versus sensitivity towards alkylating agents, and focussed on several aspects of relevance in this context, i.e. substrate selectivity, induction, inhibition and the genetic deficiency of human class mu isoenzymes.In chapter I a review is presented on properties of the glutathione S-transferases. Functions of the enzyme system and the classification of isoenzymes are discussed in section 1.1. Section 1.2 deals with aspects of GST isoenzymes influencing an individual's susceptibility towards alkylating agents, i.e. tissue distribution, developmental patterns with age, hormonal influences, induction and inhibition. Sections 1.3, 1.4 and 1.5 describe the cu