• Journal of Genetic Medicine
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• 제1권1호
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• pp.27-31
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• 1997

Steroid 21 hydroxylase deficiency is a major cause of congenital adrenal hyperplasia (CAH) and is caused by genetic impairment of the gene (CYP21B). In the human genome, CYP21B is located within the MHC class III region on the short arm of chromosome 6. Most of the genes in this region are highly polymorphic and crowded. Also the CYP21B gene is accompanied by its pseudogene (CYP21A) and tandemly arranged with two genes of fourth component of complement. This highly complex gene cluster in this area may predispose genetic instability of CYP21, i.e. mutations. In this study, tried to investigate the frequency of duplication and deletion of CYP21 and patterns of the genetic alterations of these genes.We also compared the genetic alteration in normal subjects with those of the CAH patients. The results showed that 15% of the normal korean population have duplication or deletion of CYP21. There was one normal subject with heterozygous deletion of CYP21B. Of the 5 CAH patients examined, 2 were found to show abnormal patterns. One was a large-scale gene conversion and the other a gene conversion associated with deletion involving both CYP21B and C4 locus II gene. Through this study, we carne to the conclusion that the duplication or even deletion of CYP21 and C4 might be quite a common event in the Korean population and these rearrangements must be regarded as polymorphisms. It could contribute to a high incidencs of CAH by providing a genetic pool of instable CYP21.

• Molecular & Cellular Toxicology
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• 제3권4호
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• pp.314-319
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• 2007

The effects of common variants of CYP1A2 gene (CYP1A2$^*$1C and CYP1A2$^*$1F) on the CYP1A2 activity and inducibility were controversial. The aim of the present study is to investigate the effects of CYP1A2$^*$1C and CYP1A2$^*$1F on the activity of CYP1A2 determined by urinary caffeine metabolite ratio in Koreans. As might be expected, there was large inter-individual variation (16-folds) of CYP1A2 activity ranged from 2.41 to 39.58. The mean CYP1A2 activity of smokers was significantly higher than that of non-smokers. The frequencies of CYP1A2$^*$1C (-3858A) and $^*$1F (-164A) alleles were 0.219 and 0.646, respectively. The effect of CYP1A2$^*$1C on the CYP1A2 activity was not significant. However, the CYP1A2 activity of subjects with AA genotype for CYP1A2$^*$1F allele was significantly lower than that of non-AA genotypes (CC, or CA). Interestingly, the significant effect of CYP1A2$^*$1F allele on CYP1A2 activity was not observed in nonsmokers. Our results suggest that CYP1A2$^*$1F allele rather than CYP1A2$^*$1C allele significantly influences on the inducibility of CYP1A2 in Koreans. Owing to small sample size of our study, further studies should be conducted to reveal the inter-ethnic difference or the gene-environmental interaction.

• Mass Spectrometry Letters
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• 제13권4호
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• pp.152-157
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• 2022

Schisandra chinensis and its fruits have been used as a traditional herbal medicine to treat liver dysfunction, fatigue, and chronic coughs. Several in vitro and in vivo studies suggested that dibenzocyclooctadiene lignans present in Schisandra fruits strongly inhibit CYP3A4 activity. However, reports on the inhibitory potential of dietary Schisandra supplements against CYP3A activity are limited despite their increasing consumption as dietary supplements. In this study, we evaluated the CYP3A-inhibitory potential of four dietary Schisandra supplements in human liver microsomes. At a concentration of 0.05 mg/mL, Schisandra supplements from Nature's Way, Swanson, Planetary Herbals, and Only Natural inhibited CYP3A activity by 93.9, 70.8, 33.6, and 24.8%, respectively. Nature's Way, which exhibited the strongest inhibition against CYP3A, had the highest contents of gomisin B and gomisin C, which potently inhibit CYP3A activity. The in vivo pharmacokinetics of this product should be examined to determine whether the clinical relevance of inhibiting CYP3A activity by dietary Schisandra supplementation.

• Mass Spectrometry Letters
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• 제11권4호
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• pp.113-117
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• 2020

Cytochrome P450 2J2 (CYP2J2) is a member of the cytochrome P450 superfamily, and is known to be arachidonic acid epoxygenase that mediates the formation of four bioactive regioisomers of epoxyeicosatrienoic acids (EETs). CYP2J2 is also involved in the metabolism of drugs such as albendazole, astemizole, danazol, ebastine, and terfenadine. CYP2J2 is highly expressed in the heart and cancer tissues. In this study, the inhibitory potential of ten natural products against CYP2J2 activity was evaluated using human liver microsomes and tandem mass spectrometry. Among them, bilobetin, which is a kind of biflavonoid, exhibits a strong inhibitory effect against the CYP2J2-mediated astemizole O-demethylation (IC50 = 0.73 μM) and terfenadine hydroxylation (IC50 = 0.89 μM). This result suggests that bilobetin can be used as strong CYP2J2 inhibitor in drug metabolism study.

• Journal of Microbiology and Biotechnology
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• 제25권10호
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• pp.1634-1639
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• 2015

Cytochrome P450 hydroxylase (CYP) in actinomycetes plays an important role in the biosynthesis and bioconversion of various secondary metabolites. Two unique CYPs named CYP-sb21 and CYP-pa1, which were identified from Sebekia benihana and Pseudonocardia autotrophica, respectively, were proven to transfer a hydroxyl group at the 4^th or 9^th N-methyl leucine position of immunosuppressive agent cyclosporin A (CsA). Interestingly, these two homologous CYPs showed different CsA regio-selectivities. CYP-sb21 exhibited preferential hydroxylation activity at the 4^th position over the 9^th position, whereas CYP-pa1 showed the opposite preference. To narrow down the CYP domain critical for CsA regio-selectivity, each CYP was divided into four domains, and each domain was swapped with its counterpart from the other CYP. A total of 18 hybrid CYPs were then individually tested for CsA regio-selectivity. Although most of the hybrid CYPs failed to exhibit a significant change in regio-selectivity in the context of CsA hydroxylation, hybrid CYP-pa1 swapped with the second domain of CYP-sb21 showed a higher preference for the 9^th position. Moreover, hybrid CYPsb21 containing seven amino acids from the 2nd domain of CYP-pa1 showed higher preference for the 4^th position. These results imply that the 2nd domain of CsA-specific CYP plays a critical role in CsA regio-selectivity, thereby setting the stage for biotechnological application of CsA regio-selective hydroxylation.

• 환경생물
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• 제21권1호
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• pp.1-7
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• 2003

CYP1A 유전자는 cytochrome P450 약물대사효소에 속하며 다이옥신 등의 내분비계 장애물질에 의해 농도 의존적으로 유도되어 환경오염물질에 의해 유도되는 특성을 이용하여 환경오염물질에 대해 반응하는 생물체의 유전자 발현 변화뿐만 아니라 이를 토대로 특정지역의 환경오염에 관한 정보를 얻을 수 있다. 본 논문에서는 수서환경오염과 관련하여 CYP1A유전자의 유용성을 다각도로 논의하였다.

• Molecular & Cellular Toxicology
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• 제5권4호
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• pp.346-353
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• 2009

Drug metabolism is a critical determinant of the therapeutic and adverse effects of many psychotropic drugs. The metabolism depends on the pharmacokinetics of a drug, which includes its absorption, distribution, and elimination. Psychotropic drugs are metabolized mainly by cytochrome P450 (CYP) enzymes; about 20 of these enzymes exist and they are often responsible for the rate-limiting step of drug metabolism. CYP2D6 is the best-characterized P450 enzyme that exhibits polymorphism in humans. This study determined the relationship between the CYP2D6*10 (P34S) polymorphism and the response to mirtazapine in 153 Koreans with major depressive disorder (MDD). The genotype frequencies were compared using logistic regression analysis, and between-genotype differences in the decrease in the 21-item Hamilton Depression (HAMD21) score over the 12-week treatment period were analyzed using a linear regression analysis. The proportion of remitters was lower in patients with MDD possessing the S allele than in P allele carriers after 2 weeks of mirtazapine treatment. Similarly, the reductions in the HAMD21 and Clinical Global Impression (CGI) scores in S allele carriers were smaller than those in patients with the P allele after 2 weeks of mirtazapine treatment. In the analysis of depression symptoms, the sleep and delusion scores had smaller reductions in S allele carriers. Based on the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), the psychic adverse effects of mirtazapine were associated with CYP2D6 P34S, while weight gain was not. These results suggest that CYP2D6 P34S affects the outcome of mirtazapine treatment in patients with MDD, and that this polymorphism may be a good genetic marker for predicting the clinical outcome of mirtazapine treatment.

• 생명과학회지
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• 제21권11호
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• pp.1558-1564
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• 2011

CYP2J2는 치료약물 및 아라키돈산과 같은 내인성 화합물의 대사에 중요한 역할을 수행하고 있는 효소이다. 최근, CYP2J2 단백질이 인체 종양 조직이나 종양 세포주에 과발현되어 있고, CYP2J2 효소의 작용에 의해 생성된 에폭시에이코사트리에논산(EETs)이 세포사멸을 방지한다는 것이 보고되었다. 본 연구는 시판중인 약물 120종을 대상으로 시토크롬 2J2 동종효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 인체 간 마이크로솜 시료에 아스테미졸과 NADPH 재생성계 및 약물(50 ${\mu}M$)을 첨가한 후 15분간 반응시켜 생성된 대사물을 LC/MS/MS를 이용하여 분석하여 시토크롬 2J2 동종효소 활성의 변화를 평가하였다. 그 결과 할로페리돌, 터페나딘, 아리피프라졸, 미코나졸의 순으로 CYP2J2 효소 활성 저해능을 보였다. 미코나졸은 CYP2J2에 의해 매개되는 에바스틴($IC_{50}$=11.2 ${\mu}M$) 및 터페나딘($IC_{50}$=2.2 ${\mu}M$) 대사를 강력하게 저해하였다. 터페나딘 또한 CYP2J2 매개 에바스틴 대사를 농도 의존적으로 저해하였다($IC_{50}$=13.6 ${\mu}M$). 향후, 이들 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다.

• 생약학회지
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• 제50권3호
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• pp.159-164
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• 2019

Zanthoxylum Peel is widely used as a common spice for a variety of foods. In the orient, it has also been used as traditional agents for treating diseases such as indigestion. Recently, Zanthoxylum Peel has been reported to have anti-cancer activity, anti-microbial activity, and anti-inflammatory activity. Chemical components are known sanshool compounds and xanthoxylin. In this study, we were carried out to investigate the constituents of inhibiting a drug metabolizing enzyme CYP3A4 from Zanthoxylum Peel. CYP3A4 is known as an enzyme involved in drug metabolism as monooxygenase containing the heme. As a result of experiment, we found that bergapten ($IC_{50}=18.21{\mu}M$) and quercetin ($IC_{50}=17.27{\mu}M$) isolated from EtOAc extract of Zanthoxylum Peel showed remarkable CYP3A4-inhibiting activities. Structures of the isolated active compounds were established by chemical and spectroscopic means.

• Mass Spectrometry Letters
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• 제7권4호
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• pp.106-110
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• 2016

Ginseng, a traditional herbal drug, has been used in Eastern Asia for more than 2000 years. Various ginsenosides, which are the major bioactive components of ginseng products, have been shown to exert numerous beneficial effects on the human body when co-administered with drugs. However, this may give rise to ginsenoside-drug interactions, which is an important research consideration. In this study, acassette assay was performed the inhibitory effects of 12 ginsenosides on seven cytochrome P450 (CYP) isoforms in human liver microsomes (HLMs) using LC-MS/MS to predict the herb-drug interaction. After incubation of the 12 ginsenosides with seven cocktail CYP probes, the generated specific metabolites were quantified by LC-MS/MS to determine their activities. Ginsenoside Rb1 and F2 showed strong selective inhibitory effect on CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP2B6-catalyzed bupropion hydroxylation, respectively. Ginsenosides Rd showed weak inhibitory effect on the activities of CYP2B6, 2C9, 2C19, 2D6, 3A4, and compound K, while ginsenoside Rg3 showed weak inhibitory effects on CYP2B6. Other ginsenosides, Rc, Rf, Rg1, Rh1, Rf, and Re did not show significant inhibitory effects on the activities of the seven CYPs in HLM. Owing to the poor absorption of ginsenosides after oral administration in vivo, ginsenosides may not have significant side effects caused by interaction with other drugs.