Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors

Boobis, AR; Sesardic, Dorothea; Murray, Bernard P.; Edwards, Robert J.; Singleton, Alison M.; Rich, Kim J.; Murray, Stephen A.; Torre, Rafael de la; Segura, Jordi; Pelkonen, Olavi; Pasanen, Markku; Kobayashi, Shinichi; Tu, Zhiguang; Davies, Donald S.

doi:10.3109/00498259009046835

Cited by 103 publications

(42 citation statements)

References 72 publications

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“…However, the difference may exist for a specific enzyme and organic solvent. The active site as well as incubation binding site may be different among different species (Boobis et al, 1990), as highlighted in a previous study (Eagling et al, 1998). The detailed difference for the organic solvent effects on P450 enzyme activities between rat and human needs further study.…”

Section: Resultsmentioning

confidence: 99%

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes: Fig. 1.

Li¹,

Han²,

Meng³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The effects of regular organic solvents on the metabolic activities of various human cytochromes P450 (P450s) have been reported. However, very little is known about their influence on metabolic activities mediated by P450s in the rat liver microsomes (RLM). The purpose of this study was to investigate the effects of organic solvents such as methanol, acetonitrile, dimethyl sulfoxide (DMSO), acetone, and ethanol on CYP1A, CYP2C, CYP2D, CYP2E, and CYP3A-mediated metabolism using RLM. The results showed that the activities of most rat P450 enzymes appeared to be organic solvent-dependent, and the metabolism of the tested probes were remarkably reduced when the concentration of organic solvents was up to 5% v/v, whereas most organic solvents demonstrated no significant interference when the concentration was below 1%, with the exception of DMSO. In addition, organic solvents exhibited different inhibitory effects, for example, CYP2D and CYP2E showed a significant reduction of activities at lower concentrations of organic solvents. Hence, this phenomenon should be taken into consideration when designing in vitro metabolism studies of new chemical entities. Therefore, we recommend acetonitrile as the most suitable solvent for RLM incubations, and the content of organic solvent should be kept lower than 1% v/v. IntroductionCytochromes P450 (P450s) are the principal enzymes for the oxidation of drugs, environmental pollutants, and a large number of xenobiotics, which present in many mammalian organs such as lungs, kidneys, intestines, and livers. Organic solvents are routinely used to dissolve substrates or other chemicals in the microsomal incubations for drug metabolism, P450 inhibition, and induction studies. For example, ethoxyresorufin and pentoxyresorufin are both hydrophobic substrates as the biomarkers for CYP1A1 and CYP2B1, dimethyl sulfoxide (DMSO), or ethanol/bovine serum albumin (BSA) were added to increase the solubility in rat liver microsomes (RLM) incubation system (Rutten et al., 1992). Various studies have reported the effects of common organic solvents on the in vitro P450-mediated metabolic activities in human liver microsomes (HLM), human hepatocytes, or cDNA-expressed human microsomes (Cotreau-Bibbo et al., 1996;Draper et al., 1997;Chauret et al., 1998;Hickman et al., 1998;Busby et al., 1999;Coller et al., 1999;Palamanda et al., 2000). RLM were quite commonly used during in vitro studies (Yao et al., 2008;Bae et al., 2009;Pelkonen et al., 2009;Deroussent et al., 2010); however, fewer systemic studies about the effects of organic solvents on the activities of rat P450 enzymes have been reported, and those tested in rats were limited to an old system in which the S9 and older marker substrates were used (Kawalek and Andrews, 1980). A previous study (Martignoni et al., 2006) indicated that the species-specific P450 enzymes of CYP1A, CYP2C, CYP2D, and CYP3A showed appreciable interspecies differences in terms of catalytic activity between rats and humans. Hence, the sensitivity of the P450 en...

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Section: Resultsmentioning

confidence: 99%

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes: Fig. 1.

Li¹,

Han²,

Meng³

et al. 2010

Drug Metab Dispos

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“…Boobis et al (1990) suggested the following three possible reasons for species differences in the effects of chemical inhibitors on drug metabolism in vitro: 1) the active site differs in species, 2) the isoform-catalyzing metabolism differs in species, 3) the inhibition is not via direct competition at the active site and the inhibitory site differs in species. In the present study, cDNA-expressed systems were used for screening of selectivity and comparative potency of several inhibitors.…”

Section: Resultsmentioning

confidence: 99%

SELECTIVITIES OF HUMAN CYTOCHROME P450 INHIBITORS TOWARD RAT P450 ISOFORMS: STUDY WITH cDNA-EXPRESSED SYSTEMS OF THE RAT

Kobayashi

Urashima²,

Shimada³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The aim of this study was to determine the selectivities of chemical inhibitors for human cytochrome P450 (P450) isoforms toward the corresponding rat P450 isoforms by using cDNA-expressed rat P450s (CYP1A2, CYP2A1, CYP2C6, CYP2C11, CYP2D2, CYP2E1, CYP3A1, and CYP3A2). Among the inhibitor probes for human P450s used in this study, only sulfaphenazole showed a selective inhibitory effect on the activity of the corresponding rat P450 isoform (CYP2C6). Furafylline also preferentially inhibited the activity of rat CYP1A2. However, methoxalen and ketoconazole more strongly inhibited the activities of other P450 isoforms than those of the corresponding rat P450 isoforms, CYP2A1 and CYP3A1/2, respectively. On the other hand, quinidine and aniline had little effect on the activities of the corresponding rat P450 isoforms, CYP2D2, and rat CYP2E1, respectively. These results suggest that chemical probes that have been used for human P450 isoforms do not always exhibit the same selectivity for the corresponding rat P450 isoforms. However, it appears that sulfaphenazole can be used as a selective inhibitor for rat CYP2C6. In addition, furafylline may also be a relatively selective inhibitor for rat CYP1A2.

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“…Animal studies may give important information on herb -CYP interactions, but interspecies variations in the substrate specificity, catalytic features, and amino acid sequences of CYPs may cause difficulty in extrapolating animal data to humans (Boobis et al, 1990;Lewis et al, 1998;Lin, 1995). For example, chlorzoxazone 6-hydroxylation is extensively catalyzed by CYP2E1 in humans (Halpert et al, 1994;Murray and Reidy, 1990), but also by CYP1A2 and CYP3A1 in rats (Kobayashi et al, 2002).…”

Section: Herb-cyp Interactions 41mentioning

confidence: 99%

Interactions of Herbs with Cytochrome P450

Zhou

Gao²,

Jiang

et al. 2003

Drug Metabolism Reviews

358

207

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A resurgence in the use of medical herbs in the Western world, and the co-use of modern and traditional therapies is becoming more common. Thus there is the potential for both pharmacokinetic and pharmacodynamic herb-drug interactions. For example, systems such as the cytochrome P450 (CYP) may be particularly vulnerable to modulation by the multiple active constituents of herbs, as it is well known that the CYPs are subject to induction and inhibition by exposure to a wide variety of xenobiotics. Using in vitro, in silico, and in vivo approaches, many herbs and natural compounds isolated from herbs have been identified as substrates, inhibitors, and/or inducers of various CYP enzymes. For example, St. John's wort is a potent inducer of CYP3A4, which is mediated by activating the orphan pregnane X receptor. It also contains ingredients that inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Many other common medicinal herbs also exhibited inducing or inhibiting effects on the CYP system, with the latter being competitive, noncompetitive, or mechanism-based. It appears that the regulation of CYPs by herbal products is complex, depending on the herb type, their administration dose and route, the target organ and species. Due to the difficulties in identifying the active constituents responsible for the modulation of CYP enzymes, prediction of herb -drug metabolic interactions is difficult. However, herb-CYP interactions may have important clinical and toxicological consequences. For example, induction of CYP3A4 by St. John's wort may partly provide an explanation for the enhanced plasma clearance of a number of drugs, such as cyclosporine and innadivir, which are known substrates of CYP3A4, although other mechanisms including modulation of gastric absorption and drug transporters cannot be ruled out. In contrast, many organosulfur compounds, such as diallyl sulfide from garlic, are potent inhibitors of CYP2E1; this may provide an explanation for garlic's chemoproventive effects, as many mutagens require activation by CYP2E1. Therefore, known or potential herb -CYP interactions exist, and further studies on their clinical and toxicological roles are warranted. Given that increasing numbers of people are exposed to a number of herbal preparations that contain many constituents with potential of CYP modulation, high-throughput screening assays should be developed to explore herb-CYP interactions.Key Words: Herb; Cytochrome P450; Drug interactions.Abbreviations: Ah, aryl hydrocarbon; AUC, the area of the plasma concentrationtime curve; B[a]P, benzo[a]pyrene; C max , the maximum plasma concentration; CL int , intrinsic clearance; CYP, cytochrome P450; DAD, diallyl disulfide; DAS, diallyl sulfide; DASO, diallyl sulfoxide; DASO 2 , diallyl sulfone; DPS, dipropyl sulfide; DPDS, dipropyl disulfide; K i , inhibition constant; K m , Michaelis -Menten constant; NADPH, nicotinamide adenine dinucleotide phosphate; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; N-PiP, N-nitrosopiperidine; PgP, P-glycoprotein; PhIP...

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Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors

Cited by 103 publications

References 72 publications

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes: Fig. 1.

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes: Fig. 1.

SELECTIVITIES OF HUMAN CYTOCHROME P450 INHIBITORS TOWARD RAT P450 ISOFORMS: STUDY WITH cDNA-EXPRESSED SYSTEMS OF THE RAT

Interactions of Herbs with Cytochrome P450

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