drug-mediated inactivation of cytochrome p450

Clinical and Experimental Pharmacology and Physiology (1997) 24,465-470

BRIEF REVIEW

DRUG-MEDIATED INACTIVATION OF CYTOCHROME P450

Michael Murray Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, Westmead, New South Wales,

Australia

SUMMARY

1. Multiple forms of cytochrome P450 (CUP) catalyse the oxidation of chemicals of endogenous and exogenous origin, including drugs, carcinogens, steroids and eicosanoids. However, this unusual low substrate specificity also makes CYP susceptible to inhibition by a wide range of drugs, leading to pharmacokinetic interactions of potential clinical significance.

2. Some drugs are converted by CYP to reactive metabolites that bind covalently to sites within the active centre of the same CYP. Such mechanism-based inhibition leads to CYP inactivation or complexation. These processes give rise to long- term effects on drug pharmacokinetics, as the inactivated or complexed CYP must be replaced by newly synthesized CYP protein.

3. Drugs that inactivate CYP generally possess recognizable functional groups that are oxidized to reactive products. Thus, drugs with side chains containing unsaturated carbon-carbon bonds and furan ring systems are associated with CYP inactivation. Nitrogen-containing systems may also inactivate CYP.

4. Metabolites formed from drugs containing alkylamino and methylenedioxy functionalities can trap CYP as inert complexes without eliciting inactivation. However, the functional effects of inactivation and complexation on drug pharmacokinetics are indistinguishable. Drugs that elicit CYP complexation include the first generation macrolide antibiotics, but newer analogues appear much safer. Some antidepressants, antiepileptics and tuberculostatic agents have been associated with CYP complexation.

Key words: cytochrome P450, enzyme inactivation, mechanism-based inhibition, metaboliteintermediate complexation.

INTRODUCTION

Most drugs are relatively hydrophobic and undergo biotransformation in order to terminate their therapeutic effect and facilitate their

~~ ~~

Correspondence Dr Michael Murray, Storr Liver Unit, Westmead Hospital, Westmead, NSW 2145, Australia Email <mchaelm@westmed wh su edu au>

1997 Received I2 December 1996, revision 6 March 1997, accepted 14 March

elimination from the body. The haemprotein cytochromes P450 (CUP) are major catalysts of enzymic oxidation reactions that generate hydrophilic drug metabolites. Unlike most enzymes, CYP exhibit a broad substrate specificity. This property is accounted for largely in terms of multiple CYP, but individual CYP remain extremely versatile catalysts in the oxidation of exogenous and endogenous chemicals.

Although CYP genes are distributed widely throughout most tis- sues, the liver contains the greatest concentration of those CYP that oxidize drugs efficiently. In 1987 a unifying nomenclature was proposed that classified CYP on the basis of amino acid similarity.’ The most recent compilation lists more than 500 genes and pseudogenes from all species,* but the mammalian CYP most active in hepatic drug oxidation belong to three families (CUP 1-3). Cytochromes P450 from the 1A subfamily are highly active in the oxidation of polycyclic aromatic hydrocarbons3 and CYP 1A2 also supports several drug oxidation pathways in the human liver. Important substrates include paracetamol and the~phylline.~.’ CYP2A6 participates in the oxidation of tobacco-derived nitrosamines but, as yet, few drug substrates have been identified.6 Cytochromes P450 from the 2C subfamily, especially 2C8 and 2C9, participate in the oxidation of a number of important drugs, including tolbutamide, phenytoin, torsemide and diclofenac, and CYP2C19 is the polymorphically distributed 5’-mephenytoin 4-hydroxyla~e.’~~ The expression of CYP2D6 in the liver is also polymorphically distributed’ and the enzyme is involved in the biotransformation of many drugs, most notably debrisoquine, P-adrenoceptor antagonists and narcotic

CYP2E1 oxidizes many toxic small molecules, but few drugs.” Cytochromes P450 3A are several enzymes that play a central role in the oxidation of most drugs. It has been estimated that CYP3A4 constitutes up to 50% of the total CYPin human liveri3 and that CYP3A5 is expressed in approximately 20% of the popu- 1ati0n.l~ The list of drug substrates is extensive and includes cyclosporin, macrolide antibiotics, anticancer agents, such as taxol, and many others.15 Many drugs are metabolized along several pathways involving the participation of several CYP. However, there are examples of drugs that are oxidized extensively by only a single CYP enzyme. In such cases, inhibition of CYP involved exclusively in the oxidation of particular drugs could have serious consequences for therapy. It is well appreciated, for example, that individuals who are deficient in CYP2D6 protein (poor metabolizers) are susceptible to toxicity from debrisoquine and other drug substrates for that enzyme.I6 Inhibition of CYP2D6 would be expected to produce similar adverse effects during therapy with 2D6 substrates.

466 M Murray

PHARMACOKINETIC DRUG INTERACTIONS INVOLVING CYP INHIBITION

A direct consequence of the capacity of CYP to accommodate a wide range of drug substrates is that they are susceptible to inhibition by many agents. Such processes are quite common, especially if therapy involves the concurrent administration of several drugs. However, these processes are also likely to be of short duration, perhaps characterized only by transient perturbations in the steady state concentrations of the drugs in serum. Gradual diffusion of the agent from the CYP active site would be expected to fully restore the oxidative function of the enzyme. The reversible nature of such processes indicates that the CYP enzyme does not undergo covalent modification.

In contrast with such effects, the administration of a number of drugs to patients has more serious effects on the pharmacokinetic profiles of coadministered drugs. Well described cases include the macrolide antibiotics troleandomycin and erythromycin, which are converted to reactive metabolites by CYP that bind within the catalytic centre of the Production of such reactive metabolites can lead to covalent modification of the CYP and irreversible loss of oxidative function. Indeed, new CYP must be synthesized to overcome the functional defect in drug oxidation. Several ques- tions arise, including whether it may be possible to predict the drugs that precipitate serious pharmacokinetic interactions and to identify the specific CYP that are involved in such interactions. The present review will concentrate on the process of drug-mediated inactivation of CYP with emphasis on the human situation. The underlying mechanisms of these effects will be considered, as will the consequences for concurrent administration of additional therapeutic agents.

Oxygen activation by CYP and the formation of reactive metabolites All CYP contain a common haem moiety (ferroprotoporphyrin IX) and a single polypeptide chain, which gives rise to the substrate specificity of the CYP. The polypeptide chains of each CYP are encoded by individual genes that are under distinct regulatory control.’ In order to understand why CYP can be inactivated by drugs during catalysis, it is necessary to reflect on the mechanism of electron transport and oxygen activation by these enzymes.” In the endo- plasmic reticulum, CYP are usually in the substrate-free, oxidized (ferric) state and can accommodate a drug substrate to form a bin- ary complex. The ferric CYP-substrate complex accepts an electron from the cofactor NADPH that is delivered via the coenzyme NADPH-CYP reductase. In the next step, molecular oxygen is co- ordinated at the available (sixth) ligand position of CYP. (The other five positions are occupied by lone pairs of electrons from the four porphyrin nitrogens and by the thiolate anion that attaches the haem to the polypeptide chain.) A second electron from NADPH/ NADPH-CYP reductase or NADWNADHxytochrome bs reductase enters the cycle and a transient, highly reactive form of oxygen is generated that can support substrate oxidation. The identity of the active oxidant remains uncertain, but it appears to be radical in nature.20 In most instances, drug metabolites are generated by complete circuits of the P450 cycle and dissociate from the active site. Ferric CYP is regenerated and is then available to participate in a further reaction cycle. However, because the mechanism of oxygen activation by CYP involves radical intermediates, some

substrates produce reactive metabolites. Certain metabolites inter- act directly with the haem or active site residues of the polypeptide chain of CYP so that dissociation from the catalytic centre of the cytochrome is prevented. A fundamental requirement is that the drugs must be substrates for CUP, because the parent drugs do not themselves bind tightly to CYP or elicit CYP modification.

Categories of drug-induced inactivation of CYP The term ‘mechanism-based inhibition’21 has been coined to indicate that catalysis is necessary for enzyme inhibition. The reactivity of the metabolic product prevents its escape from the CYP that catalyses its formation; this gives rise to greater specificity of inhibition as the ultimate reactive species is formed by only one or a few CYP. There is usually partitioning between detectable (non- destructive) metabolism and enzyme inactivation.

In the case of CYP enzymes there are at least two types of mechanism-dependent inhibition. The more widely studied process is CYP inactivation or suicide processing, which involves metabolism of drugs or other chemicals to products that denature the cytochrome. This may take several forms, including direct interaction with the haem or apoprotein of CYP and the generation of cross-linking between the two (haem-protein adduct formation).” The second category is metabolite-intermediate (MI) complexation of CYP in which several sequential CYP cycles produce a metabolite with the capacity to bind tightly to the CYP haem.” The distinction between suicide processing and MI complexation is that, in the latter, the haemprotein is not actually destroyed, even though it is rendered catalytically inert.” Certain generalizations can be made concern- ing the likely structural features of drugs that may lead to suicide inactivation or MI complexation.

Structural features of drugs that inactivate CYP by suicide processing

Several functional groups or arrangements of atoms within drug molecules can give rise to destructive metabolites. Drugs that possess terminal olefinic or acetylenic substituents (where the site of unsaturation is located at the terminal carbon atom of the substituent) are prime candidates as suicide substrates of CYP enzymes. Early work with 2-isopropyl-4-pentenamide (allylisopropylacetamide; AIA),23 simple terminal ethylenicZ4 and acetylenic congeners2’ and allyl-substituted barbiturate? established that oxidation by CYP converted these chemicals to radicals that alkylated the porphyrin of the cytochrome. Abnormal porphyrins have been isolated from liver or microsomal fractions and have been identified after expo- sure to such inhibitors.23324 Thus, unequivocal evidence of the mechanisms by which these agents produce haem destruction and CYP inactivation has been obtained. There are several therapeutic sub- stances that contain terminal unsaturated functional groups (Fig. l), including 17a-ethynyloestradiol and similar components of the contraceptive pil127-29 and hypnotics such as e thchlor~ynol~~ and sec- obarbitaLz6 Adverse effects produced by such drugs that could be attributable to self-inactivation of CYP include cholestasis and derangements of porphyrin m e t a b o l i ~ m . ~ ~ These effects can be explained in terms of the production of N-alkylated porphyrins and possibly also haem-protein adducts that do not undergo catabolism by the normal pathways. Fortunately, however, the incidence of such functional groups in drugs is infrequent.

P450 inactivation by drugs

OH CH

467

OH I

I CH II CHCl

17a-Ethynyloestradiol E t h c h I o rvy n o I Fig. 1. Structures of 17a-ethynyloestradiol and ethchlorvynol. These drugs contain an ethynyl moiety ( - C E CH), which undergoes cytochrome P450- mediated suicide processing to destructive metabolites.

Other kinds of molecules can also serve as mechanism-based inactivators of CYP. Thus, sulphur-containing drugs such as spironolactone are oxidized (on the sulphur atom) to a reactive intermediate, perhaps a rad i~a l .~ ' After initial interaction with the CYP prosthetic haem, a covalent adduct between the modified haem and the apoprotein of certain CYP is formed. Importantly, this kind of adduct is not produced with all CUP, even though the initial porphyrin alkylation may occur with several CYP. The features that pre- dispose some CYP to haem-protein adduct formation have not been established but, in the case of certain 4-alkyl- 1,4-dihydropyridines, the nature of the CYP active site seems irnp~rtant.~'

Cytochrome P450 destruction in mammalian liver has also been documented for a large number of apparently diverse drugs such as tienilic acid (a uricosuric the antibacterial chloramph- enic01,~~ the antipsoriatic drug methox~alen,3~ phencyclidine (a psychoactive drug of abuse),36 the antifungal agent gr i~eofulvin,~~ clorgyline and deprenyl (monoamine oxidase inhibitor^)^' and the anti-asthma drug f ~ r a f y l l i n e . ~ ~ . ~ ~ These structurally distinct agents have been directly associated with CYP inactivation (in some cases the specificity of inactivation has been assessed) or indirectly associated by drawing inferences from the porphyrinogenicity of the drugs. In some, but not all cases, the profile of effects of these agents on human hepatic CYP has been evaluated.

A number of different chemical mechanisms of drug activation appear responsible for covalent binding to CYP. In the case of the thiophene derivative tienilic acid, oxidation to the sulphoxide is considered to precede covalent binding to protein.33 Chloramphenicol is oxidized by CYP to the oxamoyl chloride analogue, which then acylates an active site lysine residue.34 Interestingly, this residue appears to be important in supporting electron transfer from the reductase to CYP because oxygen donors such as cumene hydro- peroxide or iodosylbenzene support direct substrate oxidation by the modified CYP!' The mode of CYP inactivation by methoxsalen remains underexplored. This drug inactivates human CYP extensively and studies in microsomes suggest that the furan system in

the drug may be converted to an epoxide that binds covalently to proteins. It has been proposed that phencyclidine is oxidized on the piperidinyl nitrogen to an aminium ion, which is then converted to the corresponding iminium species that binds to protein.36 Griseofulvin administration precipitates porphyria and the formation of abnormal (green) pigments in mice, but species differences in porphyrinogenicity cast doubt on the relevance of this observa- tion in humans. Furafylline, another furan derivative, is now widely used as a mechanism-based inactivator with selectivity towards human CYPlA2 but minimal activity against CYP from families 24.39.40 The drug appears to be an extremely efficient inactivator of CYPlA2 with a low incidence of metabolic side reactions. L-754 394 is an investigational drug undergoing evaluation as an inhibitor of the HIV protease!' This agent, which contains a furano- pyridinyl ring system, has been shown to inactivate CYP 3A4 and 2D6. Although the precise mechanism by which this drug inactivates CYP has not been established, its relatedness to other furans and furanocoumarins suggests that a similar mode of action may be operative; this possibility awaits further investigation. Structural sim- ilarities between methoxsalen, furafylline and L-754 394 are shown in fig. 2. It is evident from this discussion that the reactivity of CYP and the broad range of molecules that can be accommodated gives rise to the varied chemical mechanisms of drug-mediated CYP inactivation.

Structural features of drugs that inactivate CYP by MI complexation

The structural characteristics of agents that are associated with MI complexation of CYP have been explored in several studies. A major class of chemicals that form such complexes is the alkylamines. The alkylamine functionality is common to a large number of drugs, distributed across several therapeutic classes, including antidepressants, antibiotics and antihistamines. However, it is noteworthy that MI complexation is unrelated to therapeutic class and is, instead,

468 M Murray

Fig. 2. systems to epoxide metabolites of each drug.

Structure of methoxsalen (left), furafylline (centre) and L-754394 (right). Arrows indicate the potential sites of oxidation of the furan ring

,CH3 p450 . H P450 OH R - C H ~ -N: - R-CHz -N, - R-CH2-N,

CH3 CH3 CH3 1 P450

,OH Hydrolysis Yo 0 P450 f

R-CH2 -N - R-CH*-N, R-CH2-N,\ H CH2

Fig. 3. Role of cytochrome P450 (CUP) in the sequential oxidation of the general N,N-dimethylalkylamine structure to a metabolite intermediate- complex-forming species. As outlined in the text, the first CYP oxidation generates the N-monomethyl metabolite, the second oxidation forms the N- hydroxy-N-methylamine and the third step produces the nitrone, which is hydrolysed to the N-hydroxylamine, which undergoes a fourth enzymic oxidation to the nitroso analogue.

related to the capacity of the alkylamino substituent to undergo oxidation to the putative reactive metabolite.

In the case of dialkylaminoalkyl-substituted drugs, several oxidations catalysed by CYP are required to generate the reactive species, which is widely held to be the nitroso analogue (Fig. 3).4345 The first cycle mediates the N-demethylation of the disubstituted alkylamine to the monosubstituted analogue. A second oxidative step forms the N-hydroxyalkyl analogue and a third cycle oxidizes the N-hydroxyalkyl metabolite to the nitrone (N-hydroxylimino) analogue, which is hydrolysed to the N-hydroxylamine. The nitroso metabolite, which is the proximate CYP-binding species, is generated in a fourth oxidative reaction. Although nitroso formation can occur in some cases by auto- oxidation (spontaneously), the involvement of CYP is favoured. Metabolite-intermediate complexation in the presence of NADPH is rapid, whereas the non-enzymatic process is slow. Further, there is a specificity of MI complexation for some CYP: not all CYP inter- act with the nitroso analogue with equal efficiency. N-Oxidation of the secondary amine derivative seems to be preferred over primary amine oxidation; the latter has been observed, but MI

complexation from the amine is slow and inextensive compared with that from the monomethyl and N-hydroxylamine species.

An important class of MI complex-forming drugs is the macrolide antibiotics. Troleandomycin and erythromycin (14-membered macrocycle) are most commonly associated with complexation and are known to precipitate serious pharmacokinetic interactions with co-administered drugs, including jaundice with oestrogen- containing oral contraceptives, ergotism with ergot alkaloids and toxicity with theophylline!6 CYP3A enzymes in the human liver appear to be the major targets for complexation by macr01ides.l~ The central role that this enzyme has in the oxidation of most drugs and its quantitative importance underscores the potential significance of pro- tracted CYP3A inhibition. Some CYP inhibition has been reported with newer macrolides, such as josamycin (a 16-membered macrocycle):’ roxithramycin (1 4-1nernbered)~’ and clarithromycin ( 14-

but these drugs do not appear to form MI complexes. It is possible that such inhibitory processes relate more closely to the use of large doses during macrolide therapy and their relatively long half-lives. Despite these effects on drug disposition, more serious pharmacokinetic interactions are clearly associated with macrolides that generate MI complexes. It has been proposed that several factors promote the MI complex-forming capacity of macrolides, including relative hydrophobicity, and the minimiz- ation of steric hindrance around the alkylamino moiety.” Indeed, roxithromycin differs from erythromycin A only in that the !+ox0 function in the latter is replaced by an O-(2,5-dioxahexyl)oximino substituent in the former.48 However, this appears sufficient to prevent the approach of the N-alkyl substituent of roxithromycin to oxy- ferro CYP. A number of newer macrolides, including spiramycin, rokitamycin, dithromycin and azithromycin, have not been associated with significant drug interaction^.^^

The antiparkinsonian agent orphenadrine reportedly impairs its own elimination when administered to patients according to a multiple-dose regimen.” Metabolite-intermediate complexation with the major phenobarbital-inducible CYP2B enzymes has been demon- strated in rats after in vivo dosage,”’ but MI complexation of human CYP has not yet been established. Tricyclic antidepressants, such as n~rtriptyline,’~ and serotonin reuptake inhibitors, such as fluox- e t i n ~ , ~ ~ generate MI complexes in rat liver, but convincing evidence

P450 inactivation by drugs 469

for a similar process in human liver is yet to appear. It should not be assumed that CYP-specific MI complexation will be observed consistently across species.

Not all alkylamines form MI complexes. The reason for this is unclear but may be due to several factors. For example, some alkylamine drugs may have alternative routes of oxidation apart from those leading to complexation. There may be relative inefficiency of certain steps in the required reaction sequence or intermediary metabolites may be unstable. Another possibility is that steric factors may prevent the formation of the nitroso metabolite or preclude its approach to the target CYP.

Alkylamines are not the only class of chemicals that generate MI complexes with CYP. A number of methylenedioxyphenyl compounds, which are in use as pesticide synergists or were used pre- viously as flavouring agents, form very stable complexes with CYP5’ The discussion of MI complexation produced by non-therapeutic agents is beyond the scope of the present review, but it is of inter- est that stiripentol, the antiepileptic agent, also contains the methylenedioxyphenyl system and is known to inhibit CYP reactions in rat brain.s6 The inhibitory effect is apparently related to preincuba- tion of stiripentol with NADPH and microsomes, which implicates MI complexation or inactivation, but direct formation of a complex could not be established because of the low concentration of CYP in the brain. Interestingly, however, there is additional evidence for pharmacokinetic drug interactions due to stiripentol,” which suggests that the drug probably inhibits hepatic CYP as well as those in the brain.

Reactive nitrene metabolites from acylhydrazines, including the monoamine oxidase inhibitor iproniazid and the tuberculostatic drug isoniazid, also generate MI complexes with CYP.s8-6” Like alkylamine complexes, those produced from acylhydrazines are stable only in the ferrous form. Gentle oxidation of microsomes in vitro with potassium ferricyanide liberates the complexed CYP and can restore mono-oxygenase a~tivity.’~ There is no evidence that alkylamine-derived MI complexes can be similarly dissociated in vivo. In contrast, with the alkylamine or hydrazine-derived complexes, methylenedioxyphenyl metabolite complexes with ferric CYP are stable, although they can be dissociated by lipophilic substrates for cyp,S5,61.62

CONCLUSIONS The issue of specificity of CYP inactivation is an important one. If a particular reactive metabolite is generated within the active site of one or a limited number of CUP, then those enzymes are likely targets for inactivation. Inactivation of specific CYP may have major consequences for therapeutic control with drugs that are metabolized extensively by those CUP, but may have less impact on therapy with those drugs that are accommodated by several CYP. Agents that inactivate or generate MI complexes with CYP3A have perhaps the greatest potential to contribute to pharmacokinetic interactions of clinical importance.

ACKNOWLEDGEMENTS The support of the National Health and Medical Research Council and the NSW State Cancer Council is gratefully acknowledged.

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51. Labout JJM, Thijssen CT, Keijser GGJ, Hespe W. Difference between single and multiple dose pharmacokinetics of orphenadrine in man. Eur: J. Clin. Pharmacol. 1982; 21: 343-50.

52. Reidy GF, Mehta I, Murray M. Inhibition of oxidative drug metabolism by orphenadrine: In vitro and in vivo evidence for isozyme-specific complexation of cytochrome P-450 and inhibition kinetics. Mol. Pharmacol. 1989; 35: 73643.

53. Murray M. Metabolite intermediate complexation of microsomal cytochrome P450 2Cl1 in male rat liver by nortriptyline. Mol. Pharmacol. 1992; 42: 931-8.

54. Bensoussan C, Delaforge M, Mansuy D. Particular ability of cytochromes P450 3A to form inhibitory P450-iron-metabolite complexes upon metabolic oxidation of aminodrugs. Biochem. Pharmacol. 1995; 49: 591402.

55. Wilkinson CF, Murray M, Marcus CB. Interactions of methylenedioxyphenyl compounds with cytochrome P-450 and effects on micro- soma1 oxidation. Rev. Biochem. Toxicol. 1984; 6: 27-63.

56. Mesnil M, Testa B, Jenner P. In vitro inhibition by stiripentol of rat brain cytochrome P-450-mediated naphthalene hydroxylation. Xenobiotica 1988; 18: 1097-106.

57. Levy RH, Loiseau P, Guyot M et al. Stiripentol kinetics in epilepsy: Nonlinearity and interactions. Clin. Pharmacol. Ther. 1984; 36: 661-9.

58. Hines RN, Prough RA. The characterization of an inhibitory complex formed with cytochrome P-450 and a metabolite of 1,l-disubstituted hydrazines. J. Pharmacol. Exp. Ther. 1980; 214: 80-6.

59. Muakkassah SF, Bidlack WR, Yang WCT. Reversal of the effects of isoniazid on hepatic cytochrome P-450 by potassium ferricyanide. Biochem. Pharmacol. 1982; 31: 249-51.

60. Moloney SJ, Snider RJ, Prough RA. The interactions of hydrazine derivatives with rat hepatic cytochrome P-450. Xenobiotica 1984; 14: 803-14.

61. Murray M, Wilkinson CF, Marcus C, Dube CE. Structure-activity rela- tionships in the interactions of alkoxymethylenedioxyphenylbenzene derivatives with rat hepatic microsomal mixed-function oxidases in vivo. Mol. Pharmacol. 1983; 24: 129-36.

62. Murray M, Zaluzny L, Farrell GC. Selective reactivation of steroid hydroxylases following dissociation of the isosafrole metabolite complex with rat hepatic cytochrome P-450. Arch. Biochem. Biophys. 1986; 251: 411-8.

drug-mediated inactivation of cytochrome p450

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