Gillian Smith & Christoph Sachse (2001) A Role for Cyp2d6 in Nicotine Metabolism?. Psycoloquy: 12(005) Nicotine Addiction (5)

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PSYCOLOQUY (ISSN 1055-0143) is sponsored by the American Psychological Association (APA).
Psycoloquy 12(005): A Role for Cyp2d6 in Nicotine Metabolism?

A ROLE FOR CYP2D6 IN NICOTINE METABOLISM?
Target Article on Nicotine-Addiction

Gillian Smith & Christoph Sachse
Biomedical Research Centre
Ninewells Hospital & Medical School
Dundee DD1 9SY
UK

gillian.smith@icrf.icnet.uk christoph.sachse@gmx.de

Abstract

Nicotine is known to be metabolised to its major metabolite cotinine by members of the cytochrome P450 monooxygenase superfamily. Although CYP2A6 has now been identified as the principal enzyme which catalyses this biotransformation, CYP2D6 is also an active nicotine C-oxidase. Some 8% of the Caucasian population have reduced or absent CYP2A6 activity; CYP2D6 may play a significant role in nicotine metabolism in these individuals. CYP2D6 is highly polymorphic - a number of studies linking CYP2D6 genotype to smoking behaviour have now been published. CYP2D6 may have an important constitutive function in neurotransmitter metabolism and CYP2D6 genotype is thought to be a critical determinant in the success of antidepressant drug treatment.

Keywords

Nicotine, addiction, CYP2D6, cytochrome P450, genetic polymorphism, smoking behaviour.
    The target article below was today published in PSYCOLOQUY, a
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    INTRODUCTION FOR NICOTINE ADDICTION WORKSHOP BY MARCUS MUNAFO AND
    MIKE MURPHY: The ICRF General Practice Research Group in Oxford
    recently hosted a workshop on the theme of "Neuroscience, molecular
    genetics and nicotine addiction". It was chaired by Professor Neal
    Benowitz from the University of California at San Francisco, a
    specialist in the field of nicotine pharmacology spending an
    invited week in the University to work with the Group, and included
    about 30 other experts from groups around the UK and Sweden,
    including the ICRF Molecular Pharmacology Unit in Dundee and the
    ICRF Health Behaviour unit in London. Their backgrounds included
    neuroscience, molecular genetics, genetic epidemiology,
    pharmacology, psychology and clinical medicine, but they were
    united in a belief about the importance of tobacco control.

    It is now recognised that addiction to nicotine lies at the heart
    of the tobacco control problem. Without the marketing of tobacco
    its use would dwindle. But while it is so widely promoted smoking
    research focuses heavily on factors affecting why people continue
    smoking after trying it and how to get them to stop with
    psychological support and the use of effective drugs. Although
    tobacco use is rightly viewed as a social and psychological problem
    we also need to see it as a pharmacological one with a potential
    genetic contribution to the addictive process. The need to
    integrate knowledge about the brain chemistry underlying addiction,
    the molecular genetics of these cellular processes, and how the
    drugs which are effective work, was the workshop's subject.

    Each of the meeting's 4 sessions kicked off with a brief
    introduction by speakers who had precirculated draft papers. The
    sessions considered in turn: (1)how nicotine is metabolised and
    cleared from the body (2)the brain receptors in which nicotine
    "docks" to exert its effects (3)the brain pathways involving the
    neurotransmitter,dopamine,which are thought to contribute to the
    rewarding properties of nicotine which reinforce a smoker's desire
    to smoke (4)other non-dopamine pathways that are activated by
    nicotine and may underly such effects as nicotine withdrawal
    symptoms.

    Understanding how the drugs which are effective (Nicotine
    Replacement Therapy and some antidepressants) interact with the
    expression of individual genotypes in the brain and elsewhere to
    predict success in quitting smoking will help to shed light on
    which bits of the brain are important in nicotine addiction at both
    the anatomical and cellular level. The workshop participants
    emerged pleased to have caught up with advances in fields which
    were not their speciality and with a strong sense that more
    enduring closer contact and cooperation will be possible in the
    future.

I. OVERVIEW OF NICOTINE METABOLISM

1. Nicotine, the major addictive component of tobacco, is a tertiary amine which binds nicotinic cholinergic and acetylcholine receptors in the brain. Nicotine binding leads to the release of a variety of neuro- transmitters including acetylcholine, noradrenaline, dopamine and serotonin (Benowitz 1996 and references therein).

2. The major metabolite (70-80%) of nicotine is cotinine (Figure 1), the formation of which is catalysed by a cytochrome P450 enzyme, CYP2A6 (Messina et al. 1997). Although CYP2A6 is now thought to be the principal nicotine C-oxidase, certain other P450 isozymes including CYP2B6 and CYP2D6 have also shown to be active in catalysing this reaction in recombinant systems (McCracken et al. 1992; Yamazaki et al. 1999, Table 1).

    FIGURE 1: CYP2A6 catalyses the rate-limiting step in nicotine
    metabolism

ftp://www.cogsci.soton.ac.uk/pub/psycoloquy/2001.volume.12/Pictures/nic1.gif

    TABLE 1: Relative nicotine C-oxidase activities of recombinant
    human P450s expressed in baculovirus (Yamazaki et al. 1999)

    P450            Km       Vmax

    CYP2A6          11       11 
    CYP2B6          105      8.2 
    CYP2D6          132      8.6

3. The relative activities of CYP2A6 and CYP2D6 towards nicotine have also been compared by analysis of individual P450 isozyme expression in a panel of human liver microsomes by Western blotting and correlation of the level of expression of individual isozymes with nicotine C-oxidation rates (Yamazaki et al. 1999). The results of these experiments demonstrated that the strongest correlation was observed between CYP2A6 expression and enzyme activity. In addition, no inhibition of enzyme activity was observed with the CYP2D6 inhibitor quinidine, suggesting that CYP2D6 does not make a significant contribution to nicotine metabolism in human liver. This was further confirmed by the observation that the CYP2D6 phenotype of an individual known to be deficient in nicotine C-oxidation was that of an extensive metaboliser (Benowitz et al. 1995).

4. Considerable inter-individual variation has been observed in nicotine metabolism, and individuals with severely compromised nicotine C-oxidation activities identified (Benowitz et al. 1995). Recent evidence suggests that the principal defect in nicotine oxidation arises from genetic polymorphism at the CYP2A6 gene locus. Approximately 8% of the Caucasian population and 27% of Chinese appear to have diminished or absent CYP2A6 activity due to heterozygous or homozygous CYP2A6 polymorphisms (Oscarson et al. 1999). This ethnic variation in CYP2A6 allele frequencies is likely to go some way to rationalise the ethnic differences observed in nicotine and cotinine metabolism (Benowitz et al. 1999). It may be hypothesised that while the catalytic activity of CYP2D6 towards nicotine is negligible in the presence of CYP2A6, CYP2D6 may contribute to nicotine metabolism in the absence of CYP2A6.

5. Unlike CYP2A6, which is thought to play a relatively minor role in drug metabolism, CYP2D6 is known to be responsible for the metabolism of more than 25% of commonly prescribed drugs. The expression of CYP2D6 is also subject to genetic polymorphism, with an ever increasing number of allelic variants with differing catalytic properties described (Daly et al. 1996, Table 2). Approximately 7% of the Caucasian population are homozygous for a combination of several inactive CYP2D6 alleles (Sachse et al. 1997, Table 2). These individuals, "poor metabolisers (PMs)", express no functional CYP2D6 protein and therefore have a severely compromised ability to metabolise compounds which are CYP2D6 substrates. In addition, 1-3% of Caucasians are so-called "ultra-rapid metabolisers", carrying multiple copies of CYP2D6 arranged in tandem. This gene amplification can involve as many as 13 copies of CYP2D6 and results in extremely rapid substrate metabolism (Johansson et al. 1993). Like CYP2A6, the frequency of both CYP2D6 poor and ultra-rapid metabolisers varies in different ethnic groups (Table 3), with obvious consequences for prescribing regimens for the affected drugs.

    TABLE 2: Compilation of CYP2D6 alleles

    Allele name   Nucleotide          Protein    Enzyme     Allele 
    New     Old   sequence            sequence   activity   frequency
                  changes             changes                  [%]

    *1       wt   "Wild-type"          None        normal      36.4

    *2       L    1661 G>C, 2850 C>T,  R296C,      down        32.4
                  4180 G>C             S486T

    *1x2          CYP2D6 duplicated    2 active     UP         0.51
                                       genes

    *2xN     L2   CYP2D6 duplicated    N active     UP         1.34
                                       genes

    *3       A    2549 A deleted       Frameshift    0         2.04

    *4       B    100 C>T, 1846 G>A,   Frameshift    0         20.7
                  4180 G>C             of splicing 
                                       signal

    *5       D    CYP2D6 deleted       None          0         1.95
                                       expressed

    *6       T    1707 T deleted       Frameshift    0         0.93

    *9       C    2613-2615 AGA        K281        down        1.78
                  deleted              deleted

    *10      J/Ch 100 C>T, 1661 G>C,   P34S,       down        1.53
                  4180 G>C             S486T 

    Alleles of CYP2D6 (updated at
    http://www.imm.ki.se/CYPalleles/cyp2d6.htm), found to be most
    frequent among white Caucasians (frequencies from Sachse et al.
    1997). Consensus CYP2D6 gene nomenclature is according to Daly et
    al. 1996.

    TABLE 3: Ethnic differences in CYP2D6 allele frequencies

    Population  Subjects  Poor metaboli-  Allele frequency  Reference
      sample       [n]    sers (PMs)[%]     of *MxN [%]    

    Koreans        152         0.0              0.3     Roh et al. 1996
    Chinese        113         0.0              1.3     Johansson et al. 1994
    Swedes         270         8.0              1.0     Dahl et al. 1995
    Germans        589         7.0              2.0     Sachse et al. 1997
    French         265         8.4              1.9     Legrand et al. 1998
    S.Spaniards    217         2.8              3.5     Agundez et al. 1995
    Anatolians     404         1.5              5.8     Aynacioglu et al. 1997
    Saudi Arabs    101         2.0              10      McLellan et al. 1997
    Blk Ethiopians 122         1.8              16      Aklillu et al. 1995
    Blk Tanzanians 113         7.0              4.1     Wennerholm et al. 1999
    Blk Americans  246         3.3              2.4     London et al. 1997
    Nicaraguans    137         3.6              1.1     Agundez et al. 1997
    Wht Americans  464         5.8              2.2     London et al. 1997

    Population frequencies of CYP2D6 PM alleles and the ultrarapid
    CYP2D6 gene duplication in populations of different ethnic origin.
    a CYP2D6*MxN is a general designation of this allele; it includes
    duplications as well as higher amplifications (known from the
    literature: N = 2, 3, 4, ..., 13) of different alleles (known from
    the literature: M = *1, *2, *4).

II. STUDIES LINKING CYP2D6 TO SMOKING BEHAVIOUR

6. A number of studies have addressed the issue of whether CYP2D6 genotype is associated with desire to smoke (Turgeon et al. 1995; Cholerton et al. 1996) or whether genotype may reinforce smoking behaviour in committed smokers (Boustead et al. 1997). The majority of these studies do not report a strong association between CYP2D6 genotype and smoking behaviour but were, however, mostly performed before CYP2A6 was identified as the major nicotine C-oxidase.

7. Much of the data on CYP2D6 genotype in smokers are found contained within larger studies investigating the CYP2D6 polymorphism as a susceptibility factor in lung cancer. The findings of many of these studies are contradictory, however, with meta-analysis of the available data suggesting no overall association between CYP2D6 genotype and susceptibility to lung cancer, irrespective of smoking status (Christensen et al. 1997; London et al. 1997). Many early studies were additionally complicated by the use of phenotyping rather than genotyping methods to assess CYP2D6 activity.

8. Although some positive findings have been reported relating CYP2D6 genotype to smoking history, the results of these studies have, in general, been based on the analysis of relatively small populations and on qualitative rather than quantitative assessment of smoking behaviour. It is therefore difficult to confidently correlate these variables with a quantitative assessment of CYP2D6 genotype.

9. A recent study (Saarikoski et al. 2000), however, reports a significant over-representation of the CYP2D6 ultra-rapid genotype in smokers, with a two-fold increase observed in heavy smokers compared to occasional smokers (OR=2.3, 95%CI=1.2-4.4) and a four-fold increase in heavy compared to never smokers (OR=4.2, 95%CI=1.8-9.8). Although the population tested was a mixture of cancer patients and healthy controls, when all possible confounding factors were included a significant trend was still observed suggesting increased tobacco use correlated with increased CYP2D6 metabolic activity.

III. CYP2D6 - A ROLE IN NEUROTRANSMITTER METABOLISM?

10. Several independent epidemiological studies have suggested that smoking is protective against Parkinson's disease (e.g. Tzourio et al. 1997, OR=0.4). Nicotine is known to stimulate dopamine release in the substantia nigra, the area of the brain which is progressively destroyed in Parkinson's disease. CYP2D6 expression has been demonstrated in this area of the brain and a possible role for the enzyme in dopamine transport proposed (Niznik et al. 1990). CYP2D6 in vitro activity is competitively inhibited by serotonin, tryptamine and dopamine, and noncompetitively inhibited by adrenaline and noradrenaline (Martinez et al. 1997). More importantly, CYP2D6 has been shown to be active in the metabolic conversion of tyramine to dopamine (Hiroi et al. 1998), and in the metabolism of tryptamine (Martinez et al. 1997). Lack of active CYP2D6 protein in poor metabolisers may therefore result in reduced dopamine formation, a hypothesis which is supported by several epidemiological studies comparing CYP2D6 PM frequencies in PD patients and healthy controls (Smith et al. 1992; Lucotte et al. 1996). More over, CYP2D6 is known to metabolise MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Gilham et al. 1997), a contaminant of synthetic narcotics, exposure to which results in the development of Parkinson's-like symptoms - studies in animal models have demonstrated a protective effect of nicotine on neuronal loss in the substantia nigra following exposure to MPTP (Janson & Moller 1993).

11. Further evidence that CYP2D6 may have a constitutive role in neurotransmission comes from Sweden (Bertilsson et al. 1989), where CYP2D6 PMs were shown to demonstrate increased vitality, efficiency and alertness, and from a Spanish study where PMs were found to be more anxiety-prone and less successfully socialized (Llerena et al. 1993).

IV. SMOKING, CYP2D6 AND ANTIDEPRESSANT THERAPY

12. Links between smoking and depression are well documented - depressive and schizophrenic illnesses are often exacerbated by smoking cessation (Covey et al. 1990; Borrelli et al. 1996), and the higher frequency of smokers among psychiatric patients is believed to represent a self-medication mechanism (Stefanis & Kokkevi 1986). Antidepressant drugs are routinely prescribed as adjutant therapy in therapeutic intervention to aid smoking cessation. Interestingly, many of these antidepressants including nortriptyline and fluoxetine are CYP2D6 substrates (Table 4), and in vivo concentrations of many of these drugs are significantly dependent on CYP2D6 genotype (e.g. clomipramine, Bertilsson et al. 1997; desipramine, Dahl et al. 1993; nortriptyline, Dalen et al. 1998). Therefore, the CYP2D6 polymorphism is likely to be a critical determinant of the success of antidepressant drug therapy.

    TABLE 4: Drugs used in the treatment of psychiatric diseases which
    are CYP2D6 substrates

    Class of drugs  Examples

    Antidepressants:  Amitriptyline, Clomipramine, Citalopram,
                      Desipramine,Fluoxetine, Fluvoxamine, Imipramine,
                      Nortriptyline,Paroxetine, Trimipramine,
                      Venlafaxine

    Antipsychotics:   Chlorpromazine, Clozapine, Haloperidol,
                      Olanzapine, Perazine, Perphenazine, Remoxipride,
                      Risperidone, Thioridazine, Zuclopenthixol

    (Not all of these drugs are metabolised exclusively by CYP2D6)

V. CONCLUSION

13. CYP2A6, not CYP2D6 appears to play a significant role in nicotine metabolism, and should therefore be the primary target for treating nicotine addiction. However, some studies have associated smoking behaviour with CYP2D6 genotype - the potential impact of CYP2D6 in neurotransmitter metabolism suggests a further link with smoking addiction. In addition, CYP2D6 is known to metabolise the majority of commonly prescribed antidepressant drugs. Where these drugs are prescribed to facilitate smoking cessation, CYP2D6 genotype may influence individual metabolic capabilities and therefore be a critical determinant of therapeutic efficacy.

ACKNOWLEDGEMENT

The authors acknowledge the financial support of the Ministry of Agriculture, Fisheries and Food (MAFF).

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