• Animal cells and systems
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• v.13 no.4
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• pp.447-452
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• 2009

We cloned the complete complementary DNA (cDNA) of a Pacific oyster (Crassostrea gigas) cytochrome P450 (CYP450)-related protein using rapid amplification of cDNA ends (RACE). The cDNA included a 1470 bp open reading frame that began with the first ATG codon at position 103 bp and ended with a TAG stop codon at position 1573 bp (GenBank accession EF451959). The sequence had all major functional domains and characteristics of previously characterized CYP450 molecules, including the heme-binding region (FGVGRRRCVG) and putative arginine codon (R) integral to enzymatic function. An NCBI/GenBank database comparison to other CYP450 genes revealed that the deduced C. gigas CYP450 amino acid sequence is similar to that of mouse (Mus musculus) CYP450 2D/II (28%, accession AK078880), rabbit (Oryctolagus cuniculus) CYP450 2D/II (28%, AB008785), and white-tufted-ear marmoset (Callithrix jacchus) CYP450 2D (28%, AY082602). Thus, although the C. gigas CYP450 we cloned appears to belong to the 2D type of the CYP450 group, it has low similarity to this type. CYP450 mRNA expression increased over 6 h in C. gigas gills at $30^{\circ}C$ and $10^{\circ}C$, and then decreased, indicating that CYP450 plays an important role in C. gigas exposed to water temperature changes. This finding can be used as a physiological index for Pacific oysters exposed to changing water temperatures.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.238.2-239
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• 2003

The purposes of this study were to evaluate the relationship between the genetic polymorphisms in CYP2D6*10 allele, MDR1 (exon 21 and 26) gene and risperidone pharmacokinetics in healthy male Korean subjects. A single dose of 2 mg risperidone tablet was given orally to 23 healthy male Korean volunteers. Blood samples were taken during the 12 hours after the dose. Serum concentrations of risperidone and 9-hydroxyrisperidone were measured using HPLC with UV detector. 23 subjects were genotyped for CYP2D6*10 allele, MDR1 G2677 T and C3435T by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). (omitted)

• The Journal of Korean Medicine
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• v.38 no.2
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• pp.15-30
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• 2017

Objectives: Hwangryunhaedok-tang (HHT; Huanglianjiedu-tang, Orengedoku-to), a traditional herbal formula, is used for treating inflammation, hypertension, gastritis, liver dysfunction, cerebrovascular diseases, dermatitis and dementia. The objective of this study was to assess the sub-acute toxicity of HHT in Sprague-Dawley (SD) rats, and its effect on the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyltransferases (UGTs). Methods: Male and female SD rats were orally administered HHT once daily at doses of 0, 500, 1000 and 2000 mg/kg for 4 weeks. We analyzed mortality, clinical observations, body weight, food consumption, organ weights, urinalysis, hematology, serum biochemistry, and histopathology. The activities of major human CYP450s (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) and UGTs (UGT1A1, UGT1A4, and UGT2B7) were assessed using in vitro fluorescence- and luminescence-based enzyme assays, respectively. Results: No toxicologically significant changes related to the repeated administration of HHT were observed in both male and female SD rats. The no observed adverse effect level (NOAEL) value was more than 2000 mg/kg/day for both sexes. HHT inhibited the activities of human microsomal CYP1A2, CYP2C19, CYP2D6, and CYP2E1, whereas it weakly inhibited the activities of CYP2B6, CYP2C9, CYP3A4, and UGT1A1. In addition, HHT negligibly inhibited the activities of human microsomal UGT1A4 and UGT2B7 with $IC_{50}$ values in excess of $1000{\mu}g/mL$. Conclusions: Our findings indicate that HHT may be safe for repeated administration up to 4 weeks. In addition, these findings provide information on the safety and effectiveness of HHT when co-administered with conventional drugs.

• Korean Journal of Biological Psychiatry
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• v.18 no.2
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• pp.95-100
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• 2011

Objectives To evaluate the drug interactions between aripiprazole and haloperidol, authors investigated plasma concentrations of those drugs by genotypes. Method Fifty six patients with a confirmed Diagnostic and Statistical Manual of Mental Disorders 4th edition diagnosis of schizophrenia were enrolled in this eight-week, double blind, placebo-controlled study. Twenty-eight patients received adjunctive aripiprazole treatment and twenty-eight patients received placebo while being maintained on haloperidol treatment. Aripiprazole was dosed at 15 mg/day for the first 4 weeks, and then 30 mg for the next 4 weeks. The haloperidol dose remained fixed throughout the study. Plasma concentrations of haloperidol and aripiprazole were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline, week 1, 2, 4 and 8. $^*1$, $^*5$, and $^*10$ B alleles of CYP2D6 and $^*1$ and $^*3$ alleles of CYP3A5 were determined. The Student's T-test, Pearson's Chi-square test, Wilcoxon Rank Sum test and Logistic Regression analysis were used for data analysis. All tests were two-tailed and significance was defined as an alpha < 0.05. Results In the frequency of CYP2D6 genotype, $^*1/^*10$ B type was most frequent (36.5%) and $^*1/^*1$ (30.8%), $^*10B/^*10B$ (17.3%) types followed. In the frequency of CYP3A5 genotype, $^*3/^*3$ type was found in 63.5% of subjects, and $^*1/^*3$ type and $^*1/^*1$ were 30.8% and 5.8% respectively. The plasma levels of haloperidol and its metabolites did not demonstrate significant time effects and time-group interactions after adjunctive treatment of aripiprazole. The genotypes of CYP2D6 and 3A5 did not affect the plasma concentration of haloperidol in this trial. No serious adverse event was found after adding aripiprazole to haloperidol. Conclusion No significant drug interaction was found between haloperidol and aripiprazole. Genotypes of CYP2D6 and 3A5 did not affect the concentration of haloperidol after adding aripiprazole.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.10
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• pp.1391-1397
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• 2016

We investigated the hepatoprotective effects of Angelica keiskei Koidzumi extract (AK) in HepG2-overexpressing cytochrome P4502E1 (CYP2E1) and C57BL/6J mice. In HepG2 cells expressing CYP2E1, cell viability and catalase activity in the ethanol-AK co-treated group significantly increased compared to those in the ethanol-treated group. In the in vivo study with C57BL/6J mice, the AK-supplemented group with ethanol liquid diet showed significantly reduced hepatic markers, including serum aspartate aminotransferase, alanine aminotransferase, and ${\gamma}$-glutamyl transferase, compared to the ethanol group without AK supplementation. AK supplementation (20 mg/kg BW/d) also significantly attenuated reactive oxygen species generation and malondialdehyde level. Notably, a low dose of AK supplementation (20 mg/kg BW/d) suppressed expression of hepatic CYP2E1 and inhibited CYP2E1 enzyme activity. These data indicate that a low dose of AK supplementation could restrain alcohol-induced hepatic damage mediated by CYP2E1.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6101-6104
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• 2012

Background: Breast cancer accounts about one million from total annual ten million new diagnosed cases of neoplasia worldwide and is the main cause of death due to cancer in women. Tamoxifen is the most popular selective estrogen receptor modulator used in anti estrogen treatments. Tamoxifen must be converted into its metabolite endoxifen for biologic effects; this conversion process is catalysed by highly polymorphic cytochrome P450 2D6 (CYP2D6). This study surveyed copy number variation of the CYP2D6 gene and its possible correlation with Tamoxifen resistance in breast cancer patients. Methods: This case control study was performed on samples taken from 79 patients with breast cancer who used tamoxifen in Yazd and Tehran Cities, Iran. Real time reactions were conducted for 10 healthy samples using the comparative $C_t$ (Cycles threshold) method, each pair of genes being compared and samples with ratios around 1 were taken as control samples. Proliferation reactions were done by Real-Time PCR ABI Prism 7500. All registered data were transformed into SPSS 15 program and analyzed. Results: Efficiency of PCR for both CYP2D6 and ALB genes was 100%. From all 23 drug resistant patients 21.7% had one copy, 47.8% two copies and 30.4% had three copies. Also from all 56 drug sensitive patients, 26.8% had one copy, 51.8% two copies and 21.4% had three copies. The percentage of patients with one and two copies was similar between two groups but patients with three copies were more likely to belong to the drug resistant group more. Odd ratios for one and two copies were 0.759 and 0.853 respectively, indicating possible protective effects while that for three copies was 1.604. Conclusions: Based on our study there is no significant link between CYP2D6 gene copy numbers and tamoxifen resistance in women with breast cancer. But more studies considering other influencing factors appear warranted.

• Archives of Pharmacal Research
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• v.26 no.8
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• pp.631-637
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• 2003

Chloroquine has been used for many decades in the prophylaxis and treatment of malaria. It is metabolized in humans through the N-dealkylation pathway, to desethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ), by cytochrome P450 (CYP). However, until recently, no data are available on the metabolic pathway of chloroquine. Therefore, the metabolic pathway of chloroquine was evaluated using human liver microsomes and cDNA-expressed CYPs. Chloroquine is mainly metabolized to DCQ, and its Eadie-Hofstee plots were biphasic, indicating the involvement of multiple enzymes, with apparent $K_m and V_{max}$ values of 0.21 mM and 1.02 nmol/min/mg protein 3.43 mM and 10.47 nmol/min/mg protein for high and low affinity components, respectively. Of the cDNA-expressing CYPs examined, CYP1A2, 2C8, 2C19, 2D6 and 3A4/5 exhibited significant DCQ formation. A study using chemical inhibitors showed only quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4/5 inhibitor) inhibited the DCQ formation. In addition, the DCQ formation significantly correlated with the CYP3A4/5-catalyzed midazolam 1-hydroxylation (r=0.868) and CYP2C8-catalyzed paclitaxel 6$\alpha$-hydroxylation (r = 0.900). In conclusion, the results of the present study demonstrated that CYP2C8 and CYP3A4/5 are the major enzymes responsible for the chloroquine N-deethylation to DCQ in human liver microsomes.

• Childhood Kidney Diseases
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• v.26 no.1
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• pp.63-67
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• 2022

Nephrocalcinosis often occurs in infants and is caused by excessive calcium or vitamin D supplementation, neonatal primary hyperparathyroidism, and genetic disorders. Idiopathic infantile hypercalcemia (IIH), a rare cause of nephrocalcinosis, results from genetic defects in CYP24A1 or SLC34A1. Mutations in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, disrupt active vitamin D degradation. IIH clinically manifests as failure to thrive and hypercalcemia within the first year of life and usually remits spontaneously. Herein, we present a case of IIH wih CYP24A1 mutations. An 11-month-old girl visited our hospital with incidental hypercalcemia. She showed failure to thrive, and her oral intake had decreased over time since the age of 6 months. Her initial serum parathyroid hormone level was low, 25-OH vitamin D and 1,25(OH)₂ vitamin D levels were normal, and renal ultrasonography showed bilateral nephrocalcinosis. Whole-exome sequencing revealed compound heterozygous variants in CYP24A1 (NM_000782.4:c.376C>T [p.Pro126Ser] and c.1310C>A [p.Pro437His]). Although her hypercalcemia and poor oral intake spontaneously resolved in approximately 8 months, we suggested that her nephrocalcinosis and renal function be regularly checked in consideration of potential asymptomatic renal damage. Hypercalcemia caused by IIH should be suspected in infants with severe nephrocalcinosis, especially when presenting with failure to thrive.

• Journal of Preventive Medicine and Public Health
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• v.55 no.3
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• pp.280-288
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• 2022

Objectives: One of the most widely used pesticides today is chlorpyrifos (CPF). Cytochrome P450 (CYP)2B6, the most prominent catalyst in CPF bioactivation, is highly polymorphic. The objective of our study was to evaluate the role of CYP2B6^*6, which contains both 516G>T and 785A>G polymorphisms, in CPF toxicity, as represented by the concentration of 3,5,6-trichloro-2-pyridinol (TCPy), among vegetable farmers in Central Java, Indonesia, where CPF has been commonly used. Methods: A cross-sectional study was conducted among 132 vegetable farmers. Individual socio-demographic and occupational characteristics, as determinants of TCPy levels, were obtained using a structured interviewer-administered questionnaire and subsequently used to estimate the cumulative exposure level (CEL). TCPy levels were detected with liquid chromatography-mass spectrometry. CYP2B6^*6 gene polymorphisms were analyzed using a TaqMan^® SNP Genotyping Assay and Sanger sequencing. Linear regression analysis was performed to analyze the association between TCPy, as a biomarker of CPF exposure, and its determinants. Results: The prevalence of CYP2B6^*6 polymorphisms was 31% for ^*1/^*1, 51% for ^*1/^*6, and 18% for ^*6/^*6. TCPy concentrations were higher among participants with CYP2B6^*1/^*1 than among those with ^*1/^*6 or ^*6/^*6 genotypes. CYP2B6^*6 gene polymorphisms, smoking, CEL, body mass index, and spraying time were retained in the final linear regression model as determinants of TCPy. Conclusions: The results suggest that CYP2B6^*6 gene polymorphisms may play an important role in influencing susceptibility to CPF exposure. CYP2B6^*6 gene polymorphisms together with CEL, smoking habits, body mass index, and spraying time were the determinants of urinary TCPy concentrations, as a biomarker of CPF toxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3165-3172
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• 2012

Objective: Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. A large number of single nucleotide polymorphisms (SNPs) in the CYP2D6 gene have been reported to associate with cancer susceptibility. However, the results are controversial. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to summarize the evidence for associations. Methods: Studies focusing on the relationship between CYP2D6 gene polymorphisms and susceptibility to cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. Odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. Results: According to the inclusion criteria, forty-three studies with a total of 7,009 cancer cases and 9,646 healthy controls, were included in the meta-analysis. The results showed that there was a positive association between heterozygote (GC) of rs1135840 and cancer risk (OR=1.92, 95%CI: 1.14-3.21, P=0.01). In addition, we found that homozygote (CC) of rs1135840 might be a protective factor for cancer (OR=0.58, 95%CI: 0.34-0.97, P=0.04). Similarly, the G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 had negative associations with cancer risk (OR=0.69, 95%CI: 0.48-0.99, P=0.04; OR=0.60, 95%CI: 0.38-0.94, P=0.03; OR=0.50, 95%CI: 0.26-0.95, P=0.03; respectively). Conclusion: This meta-analysis suggests that CYP2D6 gene polymorphisms are involved in the pathogenesis of various cancers. The heterozygote (GC) of rs1135840 in CYP2D6 gene might increase the risk while the homozygote (CC) of rs1135840, G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 might be protective factors.