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Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development
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Drug Metabolism and Pharmacokinetics xxx (2014) 1e2
Contents lists available at ScienceDirect
Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-andpharmacokinetics
Editorial
Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development Since 2008, Drug Metabolism and Pharmacokinetics (DMPK) has been publishing Theme Issues which have attracted much attention from many scientists involved in basic science and drug development. In this issue, we have focused on drugmetabolizing enzymes other than cytochrome P450 (P450, CYP) with the theme “Significance of non-cytochrome P450 (nonP450) enzymes in basic science, clinical situations and drug development.” As Williams et al. showed in their review which focused on the contribution ratio of enzymes responsive for drugmetabolism, the most important enzyme is P-450 without doubt [1]. Accumulation of a large amount of research data on P450mediated metabolism allows a high-throughput screening system to be constructed, and it made possible for drug companies to develop compounds which are relatively resistant to P450metabolism. However, many companies have encountered cases where a drug shows an unexpectedly high clearance and poor bioavailability due to metabolism catalyzed by non-P450 enzymes. These topics were discussed in the 7th Short Course (2013, organized by Dr. Eiichi Fuse) and in a symposium at the 28th JSSX Annual Meeting (2013, organized by Drs. Miki Nakajima and Yuji Ishii). Recently, the 19th North American ISSX-29th JSSX meeting also discussed this subject at the Short Course Program (2014, organized by Drs. Teruko Imai and Jeff Jones). Although the importance of studies involving non-P450 drug-metabolizing enzymes is recognized, at the present, there is not enough information to appreciate the whole picture when compared with information about P450. Therefore, this theme issue focuses on current topics involving non-P450 drug-metabolizing enzymes, and five groups of authors, world-leading scientists, have been invited to review and discuss these enzymes and their reactions. Although many kinds of non-P450 drug-metabolizing enzymes are known, sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT), as phase II enzymes, and esterases, aldehyde dehydrogenase (AO), and flavin-containing monooxygenase (FMO), as phase I enzymes, are the subject of this special feature. The phase II enzymes are not only involved in the biotransformation of the metabolites of phase I reactions but are also involved in the metabolism of drugs directly. Further, phase II enzymes can be involved in the metabolic activation of certain drugs. In such cases, inhibition of phase II enzymes by co-prescribed medicines could be a cause of drugedrug interactions. Unlike glucuronidation, which is considered a low-affinity/high-capacity process, sulfation is a highaffinity/low capacity process that is dependent on cofactor PAPS (30 -phosphoadenosine-50 -phosphosulfate) availability. Therefore, following the depletion of the co-factor PAPS, metabolic switching from sulfation to glucuronidation can occur, and this often results
in non-linear pharmacokinetics. In the case of SULT, we asked Dr. Charles Falany (University of Alabama, USA) to review our fundamental understanding of the structure and functional relationship of SULT and also the latest cutting edge research. This review is entitled “Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis”. Recent studies have revealed the role of dimerization of SULT in catalysis. It is estimated that UGT-catalyzed glucuronidation reactions are responsible for the metabolism of approximately 35% of all drugs metabolized by phase II enzymes [2]. Therefore, UGTs make the greatest contribution as phase II enzymes and are the second most important enzymes involved in the metabolism of commercial drugs after P450. We asked Dr. Yoichi Naritomi (Astellas Pharma Inc., Japan) and Dr. Nakajima (Kanazawa University, Japan) to discuss UGT. It is very useful if the bioavailability and metabolism of candidate drugs can be predicted accurately. In vitroein vivo extrapolation (IVIVE) has been well documented for P450-mediated metabolism. However, there are relatively few studies of glucuronidation. Dr. Naritomi has provided a systematic review entitled “Prediction of hepatic and intestinal glucuronidation using in vitroein vivo extrapolation.” Dr. Nakajima has reviewed several topics from basic research to cutting edge studies on UGT including the epigenetic regulation of UGTs. The findings of Dr. Hosokawa's group have firmly established the importance of metabolism catalyzed by carboxylesterases (CESs) which form a multi-gene family [3]. Recently, Dr. Nakajima and co-workers have found a new and unique esterase involved in the hydrolysis of mycophenolic acid glucuronide. Therefore, the review also covers the topic of esterases. There is no doubt about the importance of esterases in drug development since esterasemediated metabolic activation of pro-drugs is one of the strategies to transport the active component to the target organ without loss of pharmacological activity. The title of the review by Dr. Nakajima is “A comprehensive overview of UDP-glucuronosyltransferase and esterases for drug development.” In addition, currently, the low bioavailability due to AO-related metabolism is a topic of great interest. Since one of the important strategies for drug development is to avoid P450-dependent metabolism, the structure requirements sometime satisfy the substrate specificity of AO. In the case of AO, we asked Dr. Seigo Sanoh (Hiroshima University, Japan) to review this topic since he has revealed very detailed studies on AO ranging from the basic concepts to current topics. The title of the review by Dr. Sanoh is “Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy.”
http://dx.doi.org/10.1016/j.dmpk.2014.12.004 1347-4367/Copyright © 2014, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
Please cite this article in press as: Ogura K, Ishii Y, Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development, Drug Metabolism and Pharmacokinetics (2014), http://dx.doi.org/10.1016/j.dmpk.2014.12.004
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Editorial / Drug Metabolism and Pharmacokinetics xxx (2014) 1e2
In addition, Drs. Tomomi Taniguchi (Mitsubishi Tanabe Pharma, Japan) and Makiko Shimizu (Showa Pharmaceutical University, Japan) have contributed an original article and a note on the studies of FMO, respectively. In the former case, Dr. Taniguchi has dealt with the species differences and an index for FMO. The title of the paper is “Benzydamine N-oxygenation as an index for flavincontaining monooxygenase activity and benzydamine N-demethylation by cytochrome P450 enzymes in liver microsomes from rats, dogs, monkeys, and humans.” In the latter case, Dr. Shimizu described the relevance of the polymorphism of FMO3 in the paper entitled “Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human liver.” Mutation of FMO3 gene is known to cause “Fish-odor syndrome” and is an important quality of life issue. From a drug metabolism point of view, it should be noted that genetic polymorphism of FMO3 may lead to changes of drugedrug interactions. The content of this special issue was established by a discussion in a DMPK activation committee, including Drs. Shogo Ozawa and Kouichi Yoshinari who created a working group together with us, for this theme issue. In particular, in the preparation phase of this special issue, we became very indebted to Dr. Ozawa, chair of the committee. We also thank Dr. Hiroshi Yamazaki, the editor-inchief, and Ms's Noriko Noda and Nozomi Nagafusa, DMPK editorial staff who supported us in many areas. Without their help, this special issue would not have been possible. In this special issue, we chose SULT, UGT, esterase, AO and FMO as “non-P450 drug-metabolizing enzymes” which have emerged as
being very important in drug metabolism and pharmacokinetics in drug development. We believe that this issue will help the readers of DMPK to understand the importance of non-P450 drug-metabolizing enzymes and contribute important information about the basic science, clinical aspects and drug development.
References [1] Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004;32:1201e8. [2] Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;286:487e91. [3] Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules 2008;13:412e31.
Kenichiro Ogura, Ph.D.* Q2,1 School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Japan Yuji Ishii, Ph.D. Graduate School of Pharmaceutical Sciences, Kyushu University, Japan *
Corresponding author. Available online xxx
Please cite this article in press as: Ogura K, Ishii Y, Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development, Drug Metabolism and Pharmacokinetics (2014), http://dx.doi.org/10.1016/j.dmpk.2014.12.004
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DMPK24_proof ■ 23 December 2014 ■ 1/2
Drug Metabolism and Pharmacokinetics xxx (2014) 1e2
Contents lists available at ScienceDirect
Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-andpharmacokinetics
Editorial
Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development Since 2008, Drug Metabolism and Pharmacokinetics (DMPK) has been publishing Theme Issues which have attracted much attention from many scientists involved in basic science and drug development. In this issue, we have focused on drugmetabolizing enzymes other than cytochrome P450 (P450, CYP) with the theme “Significance of non-cytochrome P450 (nonP450) enzymes in basic science, clinical situations and drug development.” As Williams et al. showed in their review which focused on the contribution ratio of enzymes responsive for drugmetabolism, the most important enzyme is P-450 without doubt [1]. Accumulation of a large amount of research data on P450mediated metabolism allows a high-throughput screening system to be constructed, and it made possible for drug companies to develop compounds which are relatively resistant to P450metabolism. However, many companies have encountered cases where a drug shows an unexpectedly high clearance and poor bioavailability due to metabolism catalyzed by non-P450 enzymes. These topics were discussed in the 7th Short Course (2013, organized by Dr. Eiichi Fuse) and in a symposium at the 28th JSSX Annual Meeting (2013, organized by Drs. Miki Nakajima and Yuji Ishii). Recently, the 19th North American ISSX-29th JSSX meeting also discussed this subject at the Short Course Program (2014, organized by Drs. Teruko Imai and Jeff Jones). Although the importance of studies involving non-P450 drug-metabolizing enzymes is recognized, at the present, there is not enough information to appreciate the whole picture when compared with information about P450. Therefore, this theme issue focuses on current topics involving non-P450 drug-metabolizing enzymes, and five groups of authors, world-leading scientists, have been invited to review and discuss these enzymes and their reactions. Although many kinds of non-P450 drug-metabolizing enzymes are known, sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT), as phase II enzymes, and esterases, aldehyde dehydrogenase (AO), and flavin-containing monooxygenase (FMO), as phase I enzymes, are the subject of this special feature. The phase II enzymes are not only involved in the biotransformation of the metabolites of phase I reactions but are also involved in the metabolism of drugs directly. Further, phase II enzymes can be involved in the metabolic activation of certain drugs. In such cases, inhibition of phase II enzymes by co-prescribed medicines could be a cause of drugedrug interactions. Unlike glucuronidation, which is considered a low-affinity/high-capacity process, sulfation is a highaffinity/low capacity process that is dependent on cofactor PAPS (30 -phosphoadenosine-50 -phosphosulfate) availability. Therefore, following the depletion of the co-factor PAPS, metabolic switching from sulfation to glucuronidation can occur, and this often results
in non-linear pharmacokinetics. In the case of SULT, we asked Dr. Charles Falany (University of Alabama, USA) to review our fundamental understanding of the structure and functional relationship of SULT and also the latest cutting edge research. This review is entitled “Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis”. Recent studies have revealed the role of dimerization of SULT in catalysis. It is estimated that UGT-catalyzed glucuronidation reactions are responsible for the metabolism of approximately 35% of all drugs metabolized by phase II enzymes [2]. Therefore, UGTs make the greatest contribution as phase II enzymes and are the second most important enzymes involved in the metabolism of commercial drugs after P450. We asked Dr. Yoichi Naritomi (Astellas Pharma Inc., Japan) and Dr. Nakajima (Kanazawa University, Japan) to discuss UGT. It is very useful if the bioavailability and metabolism of candidate drugs can be predicted accurately. In vitroein vivo extrapolation (IVIVE) has been well documented for P450-mediated metabolism. However, there are relatively few studies of glucuronidation. Dr. Naritomi has provided a systematic review entitled “Prediction of hepatic and intestinal glucuronidation using in vitroein vivo extrapolation.” Dr. Nakajima has reviewed several topics from basic research to cutting edge studies on UGT including the epigenetic regulation of UGTs. The findings of Dr. Hosokawa's group have firmly established the importance of metabolism catalyzed by carboxylesterases (CESs) which form a multi-gene family [3]. Recently, Dr. Nakajima and co-workers have found a new and unique esterase involved in the hydrolysis of mycophenolic acid glucuronide. Therefore, the review also covers the topic of esterases. There is no doubt about the importance of esterases in drug development since esterasemediated metabolic activation of pro-drugs is one of the strategies to transport the active component to the target organ without loss of pharmacological activity. The title of the review by Dr. Nakajima is “A comprehensive overview of UDP-glucuronosyltransferase and esterases for drug development.” In addition, currently, the low bioavailability due to AO-related metabolism is a topic of great interest. Since one of the important strategies for drug development is to avoid P450-dependent metabolism, the structure requirements sometime satisfy the substrate specificity of AO. In the case of AO, we asked Dr. Seigo Sanoh (Hiroshima University, Japan) to review this topic since he has revealed very detailed studies on AO ranging from the basic concepts to current topics. The title of the review by Dr. Sanoh is “Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy.”
http://dx.doi.org/10.1016/j.dmpk.2014.12.004 1347-4367/Copyright © 2014, Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
Please cite this article in press as: Ogura K, Ishii Y, Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development, Drug Metabolism and Pharmacokinetics (2014), http://dx.doi.org/10.1016/j.dmpk.2014.12.004
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Editorial / Drug Metabolism and Pharmacokinetics xxx (2014) 1e2
In addition, Drs. Tomomi Taniguchi (Mitsubishi Tanabe Pharma, Japan) and Makiko Shimizu (Showa Pharmaceutical University, Japan) have contributed an original article and a note on the studies of FMO, respectively. In the former case, Dr. Taniguchi has dealt with the species differences and an index for FMO. The title of the paper is “Benzydamine N-oxygenation as an index for flavincontaining monooxygenase activity and benzydamine N-demethylation by cytochrome P450 enzymes in liver microsomes from rats, dogs, monkeys, and humans.” In the latter case, Dr. Shimizu described the relevance of the polymorphism of FMO3 in the paper entitled “Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human liver.” Mutation of FMO3 gene is known to cause “Fish-odor syndrome” and is an important quality of life issue. From a drug metabolism point of view, it should be noted that genetic polymorphism of FMO3 may lead to changes of drugedrug interactions. The content of this special issue was established by a discussion in a DMPK activation committee, including Drs. Shogo Ozawa and Kouichi Yoshinari who created a working group together with us, for this theme issue. In particular, in the preparation phase of this special issue, we became very indebted to Dr. Ozawa, chair of the committee. We also thank Dr. Hiroshi Yamazaki, the editor-inchief, and Ms's Noriko Noda and Nozomi Nagafusa, DMPK editorial staff who supported us in many areas. Without their help, this special issue would not have been possible. In this special issue, we chose SULT, UGT, esterase, AO and FMO as “non-P450 drug-metabolizing enzymes” which have emerged as
being very important in drug metabolism and pharmacokinetics in drug development. We believe that this issue will help the readers of DMPK to understand the importance of non-P450 drug-metabolizing enzymes and contribute important information about the basic science, clinical aspects and drug development.
References [1] Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004;32:1201e8. [2] Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;286:487e91. [3] Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules 2008;13:412e31.
Kenichiro Ogura, Ph.D.* Q2,1 School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Japan Yuji Ishii, Ph.D. Graduate School of Pharmaceutical Sciences, Kyushu University, Japan *
Corresponding author. Available online xxx
Please cite this article in press as: Ogura K, Ishii Y, Significance of non-cytochrome P450 (non-P450) enzymes in basic science, clinical field and drug development, Drug Metabolism and Pharmacokinetics (2014), http://dx.doi.org/10.1016/j.dmpk.2014.12.004
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