The Effects of Single Nucleotide Polymorphisms in CYP2A13 on Metabolism of 5-Methoxypsoralen

Goto, Tatsushi; Moriuchi, Hiroshi; Fu, Xuejun; Ikegawa, Tomoyo; Matsubara, Tomio; Chang, Gang; Uno, Tomohide; Morigaki, Kenichi; Isshiki, Kunio; Imaishi, Hiromasa

doi:10.1124/dmd.110.034553

Cited by 15 publications

(17 citation statements)

References 32 publications

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“…This, together with the observation that phenobarbital and α-naphthoflavone induce 8-MOP metabolism in vivo and in vitro [36], suggest a role for P450s in 8-MOP metabolism, and an inhibitory effect of furanocoumarins on human CYP1A2 has recently been confirmed [21]. However, with the exception of the predominantly hepatic CYP2A6 [37], [38] and respiratory tract-specific CYP2A13 [23], [39], cutaneous P450s active in 8-MOP metabolism have not been characterised.…”

Section: Discussionmentioning

confidence: 86%

“…P450s have been implicated in psoralen metabolism in insects [18], [19] and vertebrates [20], where different furanocoumarin derivatives induce or inhibit multiple P450s. In contrast, human P450s involved in 8-MOP metabolism have not been fully characterised, although furanocoumarins have been shown to inhibit human CYP1A2 [21] and CYP1B1 [22], polymorphisms in CYP2A13 shown to influence the metabolism of 5-methoxypsoralen [23] and the furanocoumarin chalepsin identified as both a substrate and inhibitor of coumarin hydroxylase ( CYP2A6 ) [24].…”

Section: Introductionmentioning

confidence: 99%

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Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity

et al. 2013

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BackgroundThere are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression.ObjectivesWe investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity.MethodsWe used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity.ResultsWe showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-β-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxic metabolite(s).ConclusionOur data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity

et al. 2013

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“…1C) compared with other CYP2A13 variants. Goto et al (2010) reported that the electrophoretic mobility of the recombinant CYP2A13*4 protein in SDS-polyacrylamide gel electrophoresis gel was slightly lower than the other recombinant CYP2A13 proteins. However, there was no obvious difference observed in electrophoretic mobility among the CYP2A13 variants in SDS-polyacrylamide gel electrophoresis analysis in our study.…”

Section: Resultsmentioning

confidence: 99%

“…Some characteristics of the CYP2A13*4 enzyme have been clarified in previous reports, including a loss of P450 spectrum, low electrophoretic mobility, and an increased susceptibility to limited protein digestion Goto et al, 2010). However, the capacity of CYP2A13*4 to metabolize coumarin has not been characterized yet.…”

Section: Introductionmentioning

confidence: 99%

“…Among the CYP2A13 missense variants, CYP2A13*4 (R101Q) showed a loss of enzymatic activity in metabolizing NNK, AFB 1 , and 5-methoxypsoralen Goto et al, 2010). Some characteristics of the CYP2A13*4 enzyme have been clarified in previous reports, including a loss of P450 spectrum, low electrophoretic mobility, and an increased susceptibility to limited protein digestion Goto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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An Investigation of the Catalytic Activity of CYP2A13*4 with Coumarin and Polymorphisms of CYP2A13 in a Chinese Han Population

Liu

Hong²,

Li³

et al. 2012

Drug Metab Dispos

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ABSTRACT:CYP2A13 has been identified as an efficient catalyst for the metabolisms of coumarin, aflatoxin B 1 (AFB 1 ), and several tobacco-specific carcinogens. The reported CYP2A13 polymorphisms with missense variations have been studied for their functional consequences, and CYP2A13*4 (R101Q) variant was found to be a null enzyme in metabolizing 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), AFB 1 , and 5-methoxypsoralen. In the present study, CYP2A13*4 was expressed in Sf9 cells and evaluated for coumarin 7-hydroxylation activity. Our results demonstrated that CYP2A13*4 showed no activity in coumarin 7-hydroxylation. Furthermore, computer modeling studies were conducted to probe the mechanisms underlying the loss of catalytic activity of CYP2A13*4. The results suggested that the R101Q alteration may result in the absence of several hydrogen bonds involved in heme binding and thus lead to the loss of function in CYP2A13*4. In addition, for the first time, the distribution frequencies of all eight known CYP2A13 missense alleles were examined in a Chinese Han population. The distribution frequencies of CYP2A13*3 allele and CYP2A13*4 allele in the Chinese Han population were statistically significantly different from the reported values in Japanese. Considering that the two variants of CYP2A13 are incapable of metabolic activation of NNK and AFB 1 , the susceptibility to NNK or AFB 1 exposure between the Chinese Han population and Japanese can be different.

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Metabolism of 7‐ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants

Uno

Obe

Ogura

et al. 2012

Biopharm & Drug Disp

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CYP 2A6 is a human enzyme that metabolizes many xenobiotics including coumarin, indole, nicotine and carcinogenic nitrosamines. The gene for CYP2A6 is polymorphic. There are few data available to clarify the relationship between P450 genetic variants and the metabolism of materials in food. The CYP 2A6 wild-type protein and 13 mutants (CYP2A6.1, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.7, CYP2A6.8, CYP2A6.11, CYP2A6.15, CYP2A6.16, CYP2A6.17, CYP2A6.18, CYP2A6.21, CYP2A6.23 and CYP2A6.25) were co-expressed with NADPH-cytochrome P450 reductase in E. coli. The hydroxylase activities toward 7-ethoxycoumarin, coumarin, safrole, flavanone and hydroxyflavanone were examined. Ten types of CYP2A6 variants except for CYP2A6.2, CYP2A6.5 and CYP2A6.6 showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra and had 7-ethoxycoumarin O-deethylase activities. CYP2A6.15 and CYP2A6.18 showed higher activities for safrole 1'-hydroxylation than CYP2A6.1. CYP2A6.25 and CYP2A6.7 had lower safrole 1'-hydroxylase activities. CYP2A6.7 had lower flavanone 6- and 2'-hydroxylase activities, whereas CYP2A6.25 had higher 6-hydroxylase activity and lower 2'-hydroxylase activity. Hydroxyflavanone was metabolized by CYP2A6.25, but was not metabolized by wild-type CYP2A6.1. These results indicate that CYP2A6.25 possessed new substrate specificity toward flavonoids.

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The Effects of Single Nucleotide Polymorphisms in CYP2A13 on Metabolism of 5-Methoxypsoralen

Cited by 15 publications

References 32 publications

Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity

Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity

An Investigation of the Catalytic Activity of CYP2A13*4 with Coumarin and Polymorphisms of CYP2A13 in a Chinese Han Population

Metabolism of 7‐ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants

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