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4. Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions

Author

Maréchal, J-D, Kemp, C A, Roberts, G C K, Paine, M J I, Wolf, C R, and Sutcliffe, M J

Subjects
Models, Molecular, Cytochrome P-450 CYP2D6, Cytochrome P-450 Enzyme System, Pharmaceutical Preparations, Animals, Humans, Drug Interactions, Review, digestive system, Substrate Specificity
Abstract

The cytochromes P450 (CYPs) comprise a vast superfamily of enzymes found in virtually all life forms. In mammals, xenobiotic metabolizing CYPs provide crucial protection from the effects of exposure to a wide variety of chemicals, including environmental toxins and therapeutic drugs. Ideally, the information on the possible metabolism by CYPs required during drug development would be obtained from crystal structures of all the CYPs of interest. For some years only crystal structures of distantly related bacterial CYPs were available and homology modelling techniques were used to bridge the gap and produce structural models of human CYPs, and thereby obtain useful functional information. A significant step forward in the reliability of these models came seven years ago with the first crystal structure of a mammalian CYP, rabbit CYP2C5, followed by the structures of six human enzymes, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4, and a second rabbit enzyme, CYP2B4. In this review we describe as a case study the evolution of a CYP2D6 model, leading to the validation of the model as an in silico tool for predicting binding and metabolism. This work has led directly to the successful design of CYP2D6 mutants with novel activity-including creating a testosterone hydroxylase, converting quinidine from inhibitor to substrate, creating a diclofenac hydroxylase and creating a dextromethorphan O-demethylase. Our modelling-derived hypothesis-driven integrated interdisciplinary studies have given key insight into the molecular determinants of CYP2D6 and other important drug metabolizing enzymes.

Published
2007

5. Induced thiacloprid insensitivity in honeybees ( A pis mellifera L.) is associated with up-regulation of detoxification genes.

Author

Alptekin, S., Bass, C., Nicholls, C., Paine, M. J. I., Clark, S. J., Field, L., and Moores, G. D.

Subjects
THIACLOPRID, HONEYBEES, NEONICOTINOIDS, INSECT pest control, METABOLISM, GENETIC code, PHYSIOLOGY
Abstract

Honey bees, Apis mellifera, are markedly less sensitive to neonicotinoid insecticides containing a cyanoimino pharmacophore than to those with a nitroimino group. Although previous work has suggested that this results from enhanced metabolism of the former by detoxification enzymes, the specific enzyme(s) involved remain to be characterized. In this work, a pretreatment of honey bees with a sublethal dose of thiacloprid resulted in induced insensitivity to the same compound immediately following thiacloprid feeding. A longer pretreatment time resulted in no, or increased, sensitivity. Transcriptome profiling, using microarrays, identified a number of genes encoding detoxification enzymes that were over-expressed significantly in insecticide-treated bees compared with untreated controls. These included five P450s, CYP6BE1, CYP305D1, CYP6AS5, CYP315A1, CYP301A1, and a carboxyl/cholinesterase (CCE) CCE8. Four of these P450s were functionally expressed in Escherichia coli and their ability to metabolize thiacloprid examined by liquid chromatography-mass spectrometry (LC-MS) analysis. [ABSTRACT FROM AUTHOR]

Published
2016
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10. Validation of Model of Cytochrome P450 2D6:  An in Silico Tool for Predicting Metabolism and Inhibition

Author

Kemp, C. A., Flanagan, J. U., Eldik, A. J. van, Marechal, J.-D., Wolf, C. R., Roberts, G. C. K., Paine, M. J. I., and Sutcliffe, M. J.

Abstract

There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.

Published
2004

11. Additional file 2 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
2. Zero hunger, parasitic diseases, 3. Good health
Abstract

Additional file 2. Additional results from the population resistance comparisons including Figure S2. The distributions of paired pyrethroid susceptibility test mortality values for An. gambiae s.l. Figure S3. The distributions of paired pyrethroid susceptibility test mortality values for the An. funestus subgroup. Figure S4. The distributions of paired pyrethroid susceptibility test mortality values for four species. Figure S5. The distributions of paired susceptibility test mortality values for four species exposed to deltamethrin and a non-pyrethroid insecticide. Figure S6. Comparisons between resistance to etofenprox and five other pyrethroids in the An. gambiae complex and the An. funestus subgroup. Figure S7. Comparison of resistance to three pyrethroids within the An. gambiae complex and An. funestus subgroup. Figure S8. Comparisons of resistance to three pyrethroids in four malaria vector species. Figure S9. Comparison of resistance to deltamethrin and six insecticides from other classes. Table S4. Correlations between resistance to deltamethrin and non-pyrethroid insecticides in four African malaria vector species.

12. Additional file 1 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
inorganic chemicals, fungi, parasitic diseases, 3. Good health
Abstract

Additional file 1. Further details of the functional activity data including Table S1. Primers used for amplification of CYP6Z3 and in vitro functional characterisation. Figure S1. Fe2+-CO vs. Fe2+ difference spectrum of E. coli membranes expressing AgCYP6Z3. Table S2. IC50 values (��M) of pyrethroid insecticides. Table S3. Pyrethroid metabolism by mosquito P450s.

13. Additional file 2 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
2. Zero hunger, parasitic diseases, 3. Good health
Abstract

Additional file 2. Additional results from the population resistance comparisons including Figure S2. The distributions of paired pyrethroid susceptibility test mortality values for An. gambiae s.l. Figure S3. The distributions of paired pyrethroid susceptibility test mortality values for the An. funestus subgroup. Figure S4. The distributions of paired pyrethroid susceptibility test mortality values for four species. Figure S5. The distributions of paired susceptibility test mortality values for four species exposed to deltamethrin and a non-pyrethroid insecticide. Figure S6. Comparisons between resistance to etofenprox and five other pyrethroids in the An. gambiae complex and the An. funestus subgroup. Figure S7. Comparison of resistance to three pyrethroids within the An. gambiae complex and An. funestus subgroup. Figure S8. Comparisons of resistance to three pyrethroids in four malaria vector species. Figure S9. Comparison of resistance to deltamethrin and six insecticides from other classes. Table S4. Correlations between resistance to deltamethrin and non-pyrethroid insecticides in four African malaria vector species.

14. Additional file 3 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
parasitic diseases, 3. Good health
Abstract

Additional file 3. Further details of the analyses of resistance in Aedes populations including Table S5. Diagnostic doses and data volumes for each pyrethroid. Table S6. Correlations in resistance to different pyrethroids in Ae. aegypti samples. Table S7. Comparisons of mean mortality between pairs of pyrethroids.

15. Additional file 1 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
inorganic chemicals, fungi, parasitic diseases, 3. Good health
Abstract

Additional file 1. Further details of the functional activity data including Table S1. Primers used for amplification of CYP6Z3 and in vitro functional characterisation. Figure S1. Fe2+-CO vs. Fe2+ difference spectrum of E. coli membranes expressing AgCYP6Z3. Table S2. IC50 values (��M) of pyrethroid insecticides. Table S3. Pyrethroid metabolism by mosquito P450s.

16. Induced thiacloprid insensitivity in honeybees (Apis mellifera L.) is associated with up-regulation of detoxification genes

Author

Alptekin, S., Bass, C., Nicholls, C., Paine, M. J. I., Clark, S. J., Field, L., and Moores, G. D.

Subjects
Biochemistry & Molecular Biology, Entomology
Abstract

Honey bees, Apis mellifera, are markedly less sensitive to neonicotinoid insecticides containing a cyanoimino pharmacophore than to those with a nitroimino group. Although previous work has suggested that this results from enhanced metabolism of the former by detoxification enzymes, the specific enzyme(s) involved remain to be characterized. In this work, a pretreatment of honey bees with a sublethal dose of thiacloprid resulted in induced insensitivity to the same compound immediately following thiacloprid feeding. A longer pretreatment time resulted in no, or increased, sensitivity. Transcriptome profiling, using microarrays, identified a number of genes encoding detoxification enzymes that were over-expressed significantly in insecticide-treated bees compared with untreated controls. These included five P450s, CYP6BE1, CYP305D1, CYP6AS5, CYP315A1, CYP301A1, and a carboxyl/cholinesterase (CCE) CCE8. Four of these P450s were functionally expressed in Escherichia coli and their ability to metabolize thiacloprid examined by liquid chromatography-mass spectrometry (LC-MS) analysis.

17. Additional file 3 of Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Author

Moyes, C. L., Lees, R. S., Yunta, C., Walker, K. J., Hemmings, K., Oladepo, F., Hancock, P. A., Weetman, D., Paine, M. J. I., and Ismail, H. M.

Subjects
parasitic diseases, 3. Good health
Abstract

Additional file 3. Further details of the analyses of resistance in Aedes populations including Table S5. Diagnostic doses and data volumes for each pyrethroid. Table S6. Correlations in resistance to different pyrethroids in Ae. aegypti samples. Table S7. Comparisons of mean mortality between pairs of pyrethroids.

18. Stage specific differences in steady state levels of mRNA encoding the major surface glycoprotein of Brugia pahangi

Author

Cox-Singh, J., Paine, M. J. I., Samuel Martin, and Devaney, E.

Subjects
Membrane Glycoproteins, Base Sequence, Molecular Sequence Data, Animals, Helminth Proteins, RNA, Messenger, Brugia pahangi
Abstract

The glycoprotein, gp30, is the major soluble cuticular antigen of the adult lymphatic fiarial worm Brugia pahangi (Maizels et al., 1983, Devaney, 1988). Cookson et al., 1992 suggested that gp30 may function as an antioxidant enzyme protecting B. pahangi from the vertebrate host defence mechanism. In this communication we report that the gp30 transcript is present in each of the life cycle stages, including mosquito derived L3's, and that there is a 50 fold increase in the transcription of gp30 in young adults (28 days post infection) compared to mature adults. These findings suggest that gp30 performs a general function relevant throughout the B. pahangi life cycle and in particular to young adults.

19. Induced thiacloprid insensitivity in honeybees (Apis mellifera L.) is associated with up-regulation of detoxification genes.

Author

Alptekin S, Bass C, Nicholls C, Paine MJ, Clark SJ, Field L, and Moores GD

Subjects
Anabasine pharmacology, Animals, Bees metabolism, Cytochrome P-450 Enzyme System drug effects, Gene Expression Regulation drug effects, Insecticides pharmacology, Neonicotinoids, Pyridines pharmacology, Thiazines pharmacology, Transcriptional Activation drug effects, Bees drug effects, Cytochrome P-450 Enzyme System genetics, Inactivation, Metabolic genetics
Abstract

Honey bees, Apis mellifera, are markedly less sensitive to neonicotinoid insecticides containing a cyanoimino pharmacophore than to those with a nitroimino group. Although previous work has suggested that this results from enhanced metabolism of the former by detoxification enzymes, the specific enzyme(s) involved remain to be characterized. In this work, a pretreatment of honey bees with a sublethal dose of thiacloprid resulted in induced insensitivity to the same compound immediately following thiacloprid feeding. A longer pretreatment time resulted in no, or increased, sensitivity. Transcriptome profiling, using microarrays, identified a number of genes encoding detoxification enzymes that were over-expressed significantly in insecticide-treated bees compared with untreated controls. These included five P450s, CYP6BE1, CYP305D1, CYP6AS5, CYP315A1, CYP301A1, and a carboxyl/cholinesterase (CCE) CCE8. Four of these P450s were functionally expressed in Escherichia coli and their ability to metabolize thiacloprid examined by liquid chromatography-mass spectrometry (LC-MS) analysis., (© 2016 The Royal Entomological Society.)

Published
2016
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20. Sequence characterization of cytochrome P450 CYP6P9 in pyrethroid resistant and susceptible Anopheles funestus (Diptera: Culicidae).

Author

Matambo TS, Paine MJ, Coetzee M, and Koekemoer LL

Subjects
Amino Acid Sequence, Animals, Anopheles drug effects, Base Sequence, Cytochrome P-450 Enzyme System chemistry, Cytochromes b5 metabolism, DNA, Complementary genetics, Insecticide Resistance drug effects, Molecular Sequence Data, NADPH-Ferrihemoprotein Reductase genetics, Phylogeny, Sequence Alignment, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Anopheles enzymology, Anopheles genetics, Cytochrome P-450 Enzyme System genetics, Insecticide Resistance genetics, Pyrethrins toxicity, Sequence Analysis, DNA
Abstract

Anopheles funestus, one of the main African malaria vectors, caused a major malaria outbreak in South Africa during 1999/2000, even though South Africa had an effective vector control program in place. The outbreak was due to pyrethroid resistant An. funestus invading KwaZulu/Natal. Increased activity of cytochrome P450 (monooxygenase) was responsible for the pyrethroid resistance in this species. A monooxygenase gene, CYP6P9, was highly overexpressed in the pyrethroid-resistant strain compared with a susceptible strain. Characterization of this gene as well as the redox partners involved in the catalytic cycle of P450s was investigated. The full length of the CYP6P9 sequence was isolated, sequenced and compared between the pyrethroid-resistant and -susceptible strains. Sequence identity between the two strains was 99.3%; the sequence differences were mainly outside of the conserved regions. The functional significance is still unknown, but it is feasible that these variations are associated with differences in insecticide metabolism. A second CYP6 gene (CYP6P13) was also isolated; it shared close similarities with CYP6P9. The putative redox partners, cytochrome b(5) (cyt b(5)) and NADPH-cytochrome P450 reductase (CPR), were isolated from An. funestus (resistant strain) and showed high levels of sequence identity to other insect cyt b(5) and CPRs. Isolation of the coding sequences CYP6P9 and its cognate redox partners enables expression of functional recombinant protein for biochemical and structural analysis.

Published
2010
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