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Substrate Specificity for Rat Cytochrome P450 (CYP) Isoforms: Screening

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Substrate Specificity for Rat Cytochrome P450 (CYP) Isoforms: Screening Biochemical Pharmacology 63 2002) 889±896 Substrate speci®city for rat cytochrome P450 CYP) isoforms: screening with cDNA-expressed systems of the rat Kaoru Kobayashia,*, Kikuko Urashimaa, Noriaki Shimadab, Kan Chibaa aLaboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan bDaiichi Pure Chemicals Co. Ltd., Tokyo, Japan Received 26 March 2001; accepted 8 October 2001 Abstract In this study, we performed a screening of the speci®cities of rat cytochrome P450 CYP) isoforms for metabolic reactions known as the speci®c probes of human CYP isoforms, using 13 rat CYP isoforms expressed in baculovirus-infected insect cells or B-lymphoblastoid cells. Among the metabolic reactions studied, diclofenac 4-hydroxylation DFH), dextromethorphan O-demethylation DMOD) and midazolam 4-hydroxylation were speci®cally catalyzed by CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. These results suggest that diclofenac 4-hydroxylation, dextromethorphan O-demethylation and midazolam 4-hydroxylation are useful as catalytic markers of CYP2C6, CYP2D2 and CYP3A1/3A2, respectively. On the other hand, phenacetin O-deethylation and 7-ethoxyresoru®n O-deethylation were catalyzed both by CYP1A2 and by CYP2C6. Benzyloxyresoru®n O-dealkylation and pentoxyresoru®n O-dealkylation were also catalyzed by CYP1A2 in addition to CYP2B1. Bufuralol 10-hydroxylation was extensively catalyzed by CYP2D2 but also by CYP2C6 and CYP2C11. p-Nitrophenol 2-hydroxylation and chlorzoxazone 6-hydroxylation were extensively catalyzed by CYP2E1 but also by CYP1A2 and CYP3A1. Therefore, it is necessary to conduct further study to clarify whether these activities in rat liver microsomes are useful as probes of rat CYP isoforms. In contrast, coumarin 7-hydroxylation and S-andR-mephenytoin 40-hydroxylation did not show selectivity toward any isoforms of rat CYP studied. Therefore, activities of coumarin 7-hydroxylation and S-andR-mephenytoin 40-hydroxylation are not able to be used as catalytic probes of CYP isoforms in rat liver microsomes. These results may provide useful information regarding catalytic probes of rat CYPs for studies using rat liver microsomal samples. # 2002 Elsevier Science Inc. All rights reserved. Keywords: CYP; Rat; Substrate speci®city; cDNA-expression system; Probe; Drug metabolism 1. Introduction Although CYP enzymes make xenobiotics less toxic, the reactions frequently involve the formation of reactive CYP enzymes comprise a large family of hemoprotein intermediates or allow the leakage of free radicals capable [1], and enzymes from three families CYP1, CYP2, and of causing toxicity [3,4]. Therefore, differences in the CYP3) are mainly involved in the biotransformation of levels of individual CYP isoforms and indeed the expres- xenobiotics in both humans and rats [2]. However, con- sion of distinct isoforms signi®cantly contribute to inter- siderable differences exist in the expression and catalytic species differences in the toxicity of chemicals and the activities between human and rat CYP orthologues [2]. susceptibility to chemically induced cancer [2]. Never- theless, drug safety assessment studies, including pharma- cological and toxicological studies, have been performed * Corresponding author. Tel.: 81-43-290-2920; fax: 81-43-290-2920. using rodents although they are not necessarily excellent E-mail address: [email protected] K. Kobayashi). surrogate models for man. To assess the effects and toxi- Abbreviations: CYP, cytochrome P450; POD, phenacetin O-deethyla- tion; EROD, 7-ethoxyresorufin O-deethylation; BROD, 7-benzyloxyresor- cities of xenobiotics (i.e. developmental drugs and envir- ufin O-dealkylation; PROD, 7-pentoxyresorufin O-dealkylation; CRH, onmental chemicals), it is necessary to identify CYP coumarin 7-hydroxylation; DFH, diclofenac 4-hydroxylation; SMH, isoforms responsible for the metabolism of drugs in each S-mephenytoin 40-hydroxylation; RMH, R-mephenytoin 40-hydroxylation; species. 0 DMOD, dextromethorphan O-demethylation; BLH, bufuralol 1 -hydro- Currently, many different strategies are employed for the xylation; PNPH, p-nitrophenol 2-hydroxylation; CZH, chlorzoxazone 6-hydroxylation; MD1H, midazolam 10-hydroxylation; MD4H, midazolam unambiguous identi®cation of CYP isoforms responsible 4-hydroxylation. for the biotransformation of therapeutic agents in humans. 0006-2952/02/$ ± see front matter # 2002 Elsevier Science Inc. All rights reserved. PII: S 0006-295201)00843-7 890 K. Kobayashi et al. / Biochemical Pharmacology 63 (2002) 889±896 These include the use of CYP isoform-selective inhibitors, b5. Microsomes prepared from human B-lymphoblastoid immunoinhibitory antibodies, studies with puri®ed and cells expressing CYP2A1 lot 7) and CYP2B1 lot 6) were heterogeneously expressed CYP protein, and correlation obtained from Gentest. Recombinant CYP2A1 and CYP2E1 analyses of metabolic rates of drugs with immunoquanti- were coexpressed with NADPH-CYP oxidoreductase. Con- ®ed CYP levels or metabolic rates of speci®c substrates for trol microsomes were from insect cells infected with wild- each isoform. The use of cDNA-expressed human CYPs type baculovirus and from human B-lymphoblastoid cells has greatly facilitated the evaluation of the metabolic containing the expression vector without cDNA. The ratios speci®city of probe substrates and the identi®cation of of cytochrome c reductase activity nmol/min/mg) to CYP individual CYP isoforms involved in metabolism of drugs. content pmol CYP/mg) in each recombinant CYP isoform On the other hand, criteria and approaches for unambig- used in this study were 6 for CYP1A2, 4 for CYP2A1, uous identi®cation of individual CYP isoforms responsible 42 for CYP2A2, 7 for CYP2B1, 10 for CYP2C6, 6 for for the metabolism of drugs in rats have not been estab- CYP2C11, 27 for CYP2C12, 2 for CYP2C13, 13 for lished. This is because the speci®cities of metabolic reac- CYP2D1, 22 for CYP2D2, 10 for CYP2E1, 22 for CYP3A1 tions used as probes of rat CYP isoforms have not been and 17 for CYP3A2, respectively. thoroughly evaluated. In the present study, therefore, the metabolism of model 2.3. Incubation conditions substrates for human CYP-isoforms was examined using 13 rat CYP isoforms expressed in baculovirus-infected Activities of phenacetin O-deethylation POD), 7-ethox- insect cells or human B-lymphoblastoid cells. yresoru®n O-deethylation EROD), coumarin 7-hydroxy- lationCRH),7-benzyloxyresoru®nO-dealkylationBROD), 7-pentoxyresoru®n O-dealkylation PROD), DFH, R-and 2. Materials and methods S-mephenytoin 40-hydroxylation RMH and SMH), DMOD, bufuralol 10-hydroxylation BLH), p-nitrophenol 2-hydroxy- 2.1. Chemicals lation PNPH), chlorzoxazone 6-hydroxylation CZH), mid- azolam 10- and 4-hydroxylation MD1H and MD4H), and Bufuralol hydrochloride, 10-hydroxybufuralol and testosterone 6b-, 7a-and16a-hydroxylation were deter- 4-hydroxydiclofenac were purchased from Gentest. Mid- mined. Atypical incubation mixture 0.25 mL total volume) azolam, 10- and 4-hydroxymidazolam were gifts from contained 0.1 mM EDTA, 100 mM potassium phosphate F. Hoffmann-La Roche. Zaltoprofen was a gift from Zeria buffer pH 7.4), an NADPH-generating system 0.5 mM Pharmaceutical. Dextrorphan, R- and S-mephenytoin, NADP, 2 mM glucose-6-phosphate, 1 IU/mL of glucose- 4-hydroxymephenytoin, 6-hydroxychlorzoxazone, 6b-, 6-phosphate dehydrogenase, and 4 mM MgCl2), cDNA- 7a- and 16a-hydroxytestosterone were purchased from expressed rat CYPs and a substrate. The reaction was Ultra®ne Chemicals. 7-Benzyloxyresoru®n, chlorzoxa- initiated by the addition of the NADPH-generating system zone, dextromethorphan hydrobromide, 7-ethoxyresoru®n, following a 1-min pre-incubation at 378. All reactions were 7-pentoxyresoru®n and resoru®n were purchased from performed in the linear range with respect to CYP concen- Sigma. Cyclobarbital was purchased from Tokyo Kasei tration and incubation time. After the reaction was stopped Kogyo. NADP, glucose-6-phosphate and glucose-6-phos- by the addition of 100 mL of ice-cold acetonitrile, an phate dehydrogenase were purchased from Oriental Yeast. internal standard was added. The mixtures were centrifuged p-Nitrophenol was purchased from Nacalai Tesque Inc. at 13,000 g for 10 min, and the supernatants 100 mL) were Acetaminophen, caffeine, coumarin, diclofenac, 7-hydroxy- analyzed by HPLC as described below. The substrate coumarin, 7-hydroxy-4-methylcoumarin, p-nitrocatechol, concentration, incubation time, content of cDNA-expressed phenacetin, testosterone and HPLC-grade acetonitrile CYP and amount of internal standard used for each assay and methanol were purchased from Wako Pure Chemical are listed in Table 1. 7-Ethoxyresoru®n, 7-benzyloxyresor- Industries. u®n and 7-pentoxyresoru®n were dissolved in dimethylsulf- oxide, and this mixture was added to the incubation mixture 2.2. Microsomes at a ®nal dimethylsulfoxide concentration of 1%. Testos- terone was dissolved in methanol and added to the incuba- Microsomes prepared from baculovirus-infected insect tion mixture at a ®nal methanol concentration of 1%. cells expressing CYP1A2 lot 1), CYP2A2 lot 1), CYP2B1 Samples for POD activity were evaporated by a vacuum lot 2), CYP2C6 lot 1), CYP2C11 lot 1), CYP2C12 lot 1), evaporator for 15 min after the centrifugation, and the CYP2C13 lot 1), CYP2D1 lot 2), CYP2D2 lot 1), remaining samples 100 mL) were analyzed. CYP3A1 lot 1) and CYP3A2 lot 1) were obtained from Gentest. All recombinant CYPs were coexpressed with 2.4. HPLC analysis NADPH-CYP oxidoreductase. Recombinant
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