Cytochrome P 450 isoforms involved in melatonin metabolism in human liver microsomes

Facciolà, Gabriella; Hidestrand, Mats; Bahr, Christer von; Tybring, Gunnel

doi:10.1007/s002280000245

Cited by 116 publications

(91 citation statements)

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“…It is largely responsible for the metabolism of many important xenobiotics including caffeine, theophylline, clozapine, olanzapine, duloxetine, tacrine, riluzole, lidocaine, zolmitriptan, and tizanidine (Berthou et al, 1991;Bertilsson et al, 1994;Ha et al, 1995;Madden et al, 1995;Ring et al, 1996;Wang et al, 2000;Granfors et al, 2004a) and is partially involved in the metabolism of, for example, tricyclic antidepressants and the Risomer of warfarin Kaminsky and Zhang, 1997;Olesen and Linnet, 1997). In addition, CYP1A2 plays a central role in the metabolism of certain endogenous compounds such as melatonin, 17␤-estradiol, and uroporphyrinogen (Aoyama et al, 1990;Lambrecht et al, 1992;Facciola et al, 2001). Some animal data suggest that CYP1A2 can have important housekeeping functions, in addition to its role in drug metabolism (Smith et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions

Karjalainen¹,

Neuvonen²,

Backman³

2006

Drug Metab Dispos

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ABSTRACT:Rofecoxib was recently found to greatly increase plasma concentrations of the CYP1A2 substrate drug tizanidine in humans, but there are no published in vitro studies on the CYP1A2-inhibiting effects of rofecoxib. Our objective was to investigate whether rofecoxib is a direct-acting or metabolism-dependent inhibitor of CYP1A2 in vitro. The effect of rofecoxib on the O-deethylation of phenacetin (20 M) was studied using human liver microsomes. The effect of preincubation time on the inhibitory potential of rofecoxib was also studied, and the inhibitor concentration that supports half the maximal rate of inactivation (K I ) and the maximal rate of inactivation (k inact ) were determined. Rofecoxib is a cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug, which was recently withdrawn, possibly temporarily, from clinical use because of its cardiovascular side effects. Previous studies have shown that rofecoxib moderately increases plasma concentrations and effects of theophylline (Bachmann et al., 2003) and the R-isomer of warfarin (Schwartz et al., 2000). Quite recently, rofecoxib in therapeutic doses of 25 mg per day was found to increase more than 10-fold the plasma concentrations of the CYP1A2 substrate tizanidine in humans (Backman et al., 2006b). The effects on tizanidine pharmacokinetics suggest that rofecoxib can be a relatively potent inhibitor of CYP1A2. However, hitherto, there have been no published in vitro studies on the effect of rofecoxib on CYP1A2 activity, nor has the type of CYP1A2 inhibition by rofecoxib been clarified.Rofecoxib itself is extensively metabolized via complex oxidative, reductive, and back-reduction pathways (Fig. 1) (Merck & Co., 2002;Slaughter et al., 2003). In human liver microsomal incubations, rofecoxib has been found to be metabolized to 5-hydroxyrofecoxib by several P450 enzymes, CYP1A2 and CYP3A4 having the greatest contributions . In liver S9 fractions, the metabolite profile of rofecoxib has been more complex, including the formation of both 5-hydroxyrofecoxib and different 3,4-dihydrohydroxy acid derivatives; the latter are considered to represent the major pathways in vivo (Halpin et al., 2002). Thus, it has been suggested that P450 enzymes play a minor role in rofecoxib's metabolism. However, in our recent study, the plasma concentrations of rofecoxib correlated to the plasma caffeine-paraxanthine ratio in vivo, suggesting a role for CYP1A2 in the metabolism of rofecoxib (Backman et al., 2006b). Our purpose, in the current study, was to explore in vitro the CYP1A2-inhibitory potency of rofecoxib and to elucidate the type of possible CYP1A2 inhibition. Materials and Methods Chemicals and Microsomes. Rofecoxib (Sequoia Research ProductsLimited, Pangbourne, UK), phenacetin, acetaminophen, ␤-NADPH (SigmaAldrich, St. Louis, MO), methanol, acetonitrile, and ethyl acetate (Rathburn Chemicals Ltd., Walkerburn, Scotland) were used in this study. Other chemicals were obtained from Merck (Darmstadt, Germany). Pooled human liver microsomes were obtained from BD ...

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Section: Discussionmentioning

confidence: 99%

Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions

Karjalainen¹,

Neuvonen²,

Backman³

2006

Drug Metab Dispos

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“…6 The involvement of CYP2C9 in the metabolism of melatonin has also been suggested. 7 CYP2C9 together with another CYP2C subfamily member, CYP2C8, is located in the 10q24 region. In addition, a linkage between CYP2C9 and CYP2C8 genetic polymorphisms has been reported.…”

Section: Introductionmentioning

confidence: 99%

CYP2C9 gene and susceptibility to major depressive disorder

et al. 2003

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Alteration of monoaminergic neurotransmission has been implicated in the pathophysiology of mood disorders, and CYP2C9 enzyme activity has been shown to be modulated by serotonin in vitro. The present study was aimed at analysing the frequency of CYP2C9 alleles (*1, *2, *3) among patients suffering from major depressive disorder. In all, 70 such suffering psychiatric outpatients were studied. The CYP2C9 genotypes were determined by allelespecific PCR. The CYP2C9*3 allele frequency was higher (Po0.01) among the patients suffering from major depression than in a population of 89 schizophrenic patients (odds ratio¼3.3) and 138 healthy volunteers (odds ratio¼2.8). The results suggest that CYP2C9 genetic polymorphism may be related to a major depressive disorder due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out.

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“…In this study, to determine substrate specificity of dog CYP1A2 and to compare the substrate specificity between dogs and humans, in vitro metabolism studies using the following 11 P450 substrates in CYP1A2-deficient dog, wild-type dog, and human liver microsomes were conducted: phenacetin, ethoxyresorufin, tacrine, and caffeine for exogenous human CYP1A2 substrates; melatonin, 9-cis-retinal, and estradiol for endogenous human CYP1A2 substrates; and aminopyrine, aniline, bufuralol, and midazolam for other P450 substrates (Rendic and Di Carlo, 1997;Yamazaki et al, 1998;Zhang et al, 2000;Facciolá et al, 2001). …”

mentioning

confidence: 99%

Characterization of Substrate Specificity of Dog CYP1A2 Using CYP1A2-Deficient and Wild-Type Dog Liver Microsomes

Mise

Hashizume²,

Komuro³

2008

Drug Metab Dispos

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ABSTRACT:Beagle dogs are commonly used for toxicological and pharmacological studies of drug candidates in the pharmaceutical industry. Recently, we reported a CYP1A2-deficient dog with a nonsense mutation (C1117T). In this study, using CYP1A2-deficient and wildtype dog liver microsomes, substrate specificity of dog CYP1A2 was investigated and compared with human CYP1A2. For this purpose, 11 cytochrome P450 assays were conducted in human or dog liver microsomes, genotyped for the CYP1A2 C1117T mutation. There was no statistical difference between C/C, C/T, and T/T dogs in activities of aminopyrine N-demethylase, aniline hydroxylase, bufuralol 1-hydroxylase, and midazolam 1-hydroxylase. On the other hand, activities of phenacetin O-deethylase, ethoxyresorufin O-deethylase, and tacrine 1-hydroxylase, which were catalyzed by human CYP1A2, were significantly lower in T/T dogs than C/C dogs, indicating that dog and human CYP1A2 was responsible for these activities. However, dog CYP1A2 was not involved in caffeine metabolism, a marker activity for human CYP1A2. As for endogenous substances, our results indicated that human CYP1A2, but not dog CYP1A2, is responsible for melatonin 6-hydroxylase, 9-cis-retinal oxidase, and estradiol 2-hydroxylase activity. In conclusion, tacrine, ethoxyresorufin, and phenacetin are probe substrates for CYP1A2 not only in humans but also in dogs. However, caffeine, melatonin, 9-cis-retinal, and estradiol, which are substrate for human CYP1A2, are not good substrates for dog CYP1A2. The finding that there are species differences in substrate specificity of CYP1A2 between humans and beagle dogs is an important issue and must be considered for preclinical studies using beagle dogs.

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Cytochrome P 450 isoforms involved in melatonin metabolism in human liver microsomes

Cited by 116 publications

References 0 publications

Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions

Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions

CYP2C9 gene and susceptibility to major depressive disorder

Characterization of Substrate Specificity of Dog CYP1A2 Using CYP1A2-Deficient and Wild-Type Dog Liver Microsomes

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