• Biomolecules & Therapeutics
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• 제1권1호
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• pp.50-57
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• 1993

This study characterized the effect of liver injury produced by hepatotoxicants on the biliary and urinary excretion of acetaminophen(AA) metabolites. Liver damage was produced in male S.-D. rats, 24 hr after dosing with carbon tetrachloride(4CCl_4,$ 0.75 mι/kg, ip) or thioacetamide(TA, 200 mg/kg, ip), or 16 hr after administration of cadmium chloride(4CdCl_2,$ 3.9 mg/kg, iv). Liver damage without renal injury was confirmed by measuring serum enzymes, creatinine and BUN levels as well as by histopathological examination. AA and its metabolites were measured for 3 hr by HPLC in rats injected iv with 1 mmo1/kg of AA. The excreted amounts of AA-glucuronide into bile were reduced to 60~70% of control rats by hepatotoxicants, but did not change urinary excretion of AA-glucuronide and AA-sulfate. Treatments with $CCl_4,\; CdCl_2$ and TA decreased the total (biliary plus urinary) excretion of thioethers of AA(30~50% of control), suggesting that these toxicants decrease cytochrome P-450-mediated toxification of AA. However, treatments of $CdCl_2$and TA markedly enhanced the excretion of AA-mercapturate into urine. Thus, 4CdCl_2$ and TA not only influence the formation of AA-glutathione, but may also alter the excretory routes (i.e. bile and urine) for the elimination of AA-metabolite.

• 대한의생명과학회지
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• 제19권4호
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• pp.310-314
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• 2013

CYP2E1 in the liver has been studied intensively because it is involved in the metabolic activation of xenobiotics. It is inducible by alcohol, so it has been suspected as the cause of cancer in the stomach and lung. The possible role of CYP2E1 has been suggested strongly as causing tissue damage in mice with renal failure. It was also suspected that 5'-flanking region of CYP2E1 gene might be involved with renal failure. So, we investigated polymorphism of restriction enzyme sites within CYP2E1 gene using the PCR-RFLP analysis. PstI and RsaI sites were located at 5'-flanking region and DraI site was located at intron 6. All three types (W/W, W/S, S/S) were observed for these enzymes although each incidence was somewhat different depending the enzyme sites. W/W was prominent for PstI whereas W/S was markedly high for RsaI. Overall, polymorphic incidence in patients was somewhat higher than normal population. This research should facilitate further investigation of CYP2E1 at genetic level as the direct cause of tissue damage in various organs.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.301-307
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• 2011

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $17.1{\mu}M$. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve ($AUC_{0-\infty}$) and the peak plasma concentration ($C_{max}$) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

• 한국식품영양과학회지
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• 제31권3호
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• pp.500-505
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• 2002

뇌조직에서 고혈당으로 인한 산화적 스트레스에 대한 민들레의 유해 활성산소 생성과 제거효소계에 미치는 영향을 알아보고자 streptozotocin으로 당뇨를 유발한 Wistar계 횐쥐에게 민들레의 잎과 뿌리의 분말과 열수추출물을 각각 4주간 급여하였다. 실험결과 유해 활성산소 생성효소계인 시토크롬 P450 함량, aminopyrine N-demethylase, aniline hydroxylase 및 xanthine oxidase 활성은 당뇨를 유발한 대조군에 비하여 서양민들레 잎과 뿌리 급여군 모두 감소되었다. Superoxide dismutase, catalase와 glutathione peroxidase 활성 역시 서양민들레의 분말과 열수추출물 급여시 대조군에 비하여 유의적인 감소를 나타내었으며 민들레의 부위에 따른 차이는 관찰되지 않았다. 반면 뇌조직 중의 glutathione S-transferase 활성과 GSH 함량은 대조군에 비 하여 서양민들레 급여시 유의적으로 증가되었으며, 과산화지질 함량은 당뇨 대조군에 비하여 서양민들레 급여군 모두 유의적인 감소를 보였다. 이상의 결과에서 서양민들레의 잎과 뿌리의 급여는 당뇨로 인한 횐쥐의 뇌조직 중 유리기 생성과 지질과산화로 인한 합병증 예방에 효과적일 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3761-3768
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• 2013

Background: The Saudi population has experienced a sharp increase in colorectal and gastric cancer incidences within the last few years. The relationship between gene polymorphisms of xenobiotic metabolizing enzymes and colorectal cancer (CRC) incidence has not previously investigated among the Saudi population. The aim of the present study was to investigate contributions of CYP1A1, CYP2E1, and GSTM1 gene polymorphisms. Materials and Methods: Blood samples were collected from CRC patients and healthy controls and genotypes were determined by polymerase chain reaction restriction fragment length polymorphism and sequencing. Results and Conclusions: $CYP2E1^*6$ was not significantly associated with CRC development (odd ratio=1.29; confidence interval 0.68-2.45). A remarkable and statistically significant association was observed among patients with $CYP1Awt/^*2A$ (odd ratio=3.65; 95% confidence interval 1.39-9.57). The $GSTM1^*0/^*0$ genotype was found in 2% of CRC patients under investigation. The levels of CYP1A1, CYP2E1 and GSTM1 mRNA gene expression were found to be 4, 4.2 and 4.8 fold, respectively, by quantitative real time PCR. The results of the present case-control study show that the studied Saudi population resembles Caucasians with respect to the considered polymorphisms. Investigation of genetic risk factors and susceptibility gene polymorphisms in our Saudi population should be helpful for better understanding of CRC etiology.

• 한국미생물·생명공학회지
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• 제38권4호
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• pp.475-480
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• 2010

Actinomycetes are Gram-positive soil bacteria and one of the most important industrial microorganisms due to superior biosynthetic capabilities of many valuable secondary metabolites as well as production of various valuable bioconversion enzymes. Among them are cytochrome P450 hydroxylase (CYP), which are hemoproteins encoded by a super family of genes, are universally distributed in most of the organisms from all biological kingdoms. Actinomycetes are a rich source of soluble CYP enzymes, which play critical roles in the bioactivation and detoxification of a wide variety of metabolite biosynthesis and xenobiotic transformation. Cyclosporin A (CyA), one of the most commonly-prescribed immunosuppressive drugs, was previously reported to be hydroxylated at the position of 4th N-methyl leucine by a rare actinomycetes called Sebekia benihana, leading to display different biological activity spectrum such as loss of immunosuppressive activities yet retaining hair growth-stimulating side effect. In order to improve this regio-selective CyA hydroxylation in S. benihana, previously-identified several secondary metabolite up-regulatory genes from Streptomyces coelicolor and S. avermitilis were heterologously overexpressed in S. benihana using an $ermE^*$ promoter-containing Streptomyces integrative expression vector. Among tested, SCO4967 encoding a conserved hypothetical protein significantly stimulated region-specific CyA hydroxylation in S. benihana, implying that some common regulatory systems functioning in both biosynthesis and bioconversion of secondary metabolite might be present in different actinomycetes species.

• Preventive Nutrition and Food Science
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• 제19권4호
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• pp.268-273
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• 2014

The induction of detoxification enzymes by benzyl isothiocyanate (BITC) and its synthetic N-acetyl-L-cysteine (NAC) conjugate (NAC-BITC) was examined in Hepa1c1c7 murine hepatoma cells. BITC and NAC-BITC inhibited Hepa1c1c7 cell growth in a dose-dependent manner. Cell growth was 4.5~57.2% lower in Hepa1c1c7 cells treated with $0.1{\sim}1.0{\mu}M$ BITC than in control-treated Hepa1c1c7 cells. The NAC-BITC treatment had a similar inhibitory pattern on Hepa1c1c7 cell growth; $0.5{\mu}M$ and $10{\mu}M$ NAC-BITC decreased cell growth by 13.6% and 47.4%, respectively. Treatment of Hepa1c1c7 cells with $0.1{\sim}2.0{\mu}M$ BITC also elicited a dose-response effect on the induction of quinone reductase quinone reductase (QR) activity and QR mRNA expression. Treatment with $1{\mu}M$ and $2{\mu}M$ BITC caused 1.8- and 2.8-fold inductions of QR mRNA, respectively. By comparison, treatment with $1{\mu}M$ and $2{\mu}M$ NAC-BITC caused 1.6-and 1.9-fold inductions of QR mRNA, respectively. Cytochrome P450 (CYP) 1A1 and CYP2E1 induction were lower in $0.1{\sim}2{\mu}M$ BITC-treated cells than in control-treated cells. CYP2E1 activity was 1.2-fold greater in $0.1{\mu}M$ NAC-BITC-treated cells than in control-treated cells. However, the CYP2E1 activity of cells treated with higher concentrations (i.e., $1{\sim}2{\mu}M$) of NAC-BITC was similar to the activity of control-treated cells. Considering the potential of isothiocyanatesto prevent cancer, these results provide support for the use of BITC and NAC-BITC conjugates as chemopreventive agents.

• Archives of Pharmacal Research
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• 제27권5호
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• pp.547-553
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• 2004

The pyrrolizidine alkaloids (PAs), contained in a number of traditional remedies in Africa and Asia, show wide variations in metabolism between animal species but little work has been done to investigate differences between animal strains. The metabolism of the PA senecionine (SN) in Fischer 344 (F344) rats has been studied in order to compare to that found in the previously investigated Sprague-Dawley (SO) rats (Drug Metab. Dispos. 17: 387, 1989). There was no difference in the formation of ($\pm$) 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP, bioactivation) by hepatic microsomes from either sex of SO and F344 rats. However, hepatic microsomes from male and female F344 rats had greater activity in the Noxidation (detoxication) of SN by 88% and 180%, respectively, when compared to that of male and female SD rats. Experiments conducted at various pH showed an optimum pH of 8.5, the optimal pH for flavin-containing monooxygenase (FMO), for SN N-oxidation by hepatic microsomes from F344 females. In F344 males, however, a bimodal pattern was obtained with activity peaks at pH 7.6 and 8.5 reflecting the possible involvement of both cytochrome P450 (CYP) and FMO. Use of specific inhibitors (SKF525A, 1-benzylimidazole and methimazole) showed that the N-oxide of SN was primarily produced by FMO in both sexes of F344 rats. In contrast, SN N-oxide formation is known to be catalyzed mainly by CYP2C11 rather than FMO in SD rats. This study, therefore, demonstrated that there were substantial differences in the formation of SN N-oxide by hepatic microsomes from F344 and SD rats and that this detoxification is catalyzed primarily by two different enzymes in the two rat strains. These findings suggest that significant variations in PA biotransformation can exist between different animal strains.

• Asian-Australasian Journal of Animal Sciences
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• 제25권6호
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• pp.794-799
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• 2012

The cytochrome P450c17-I (CYP17-I) is one of the enzymes critical to gonadal development and the synthesis of androgens. Two single nucleotide polymorphisms (SNPs) were detected within the coding region of the CYP17-I gene in a population of 75 male Japanese flounder (Paralichthys olivaceus). They were SNP1 (c.C445T) located in exon2 and SNP2 (c.T980C (p.Phe307Leu)) located in exon5. Four physiological indices, which were serum testosterone (T), serum $17{\beta}$-estradiol ($E_2$), Hepatosomatic index (HSI), and Gonadosomatic index (GSI), were studied to examine the effect of the two SNPs on the reproductive endocrines of Japanese flounder. Multiple comparisons revealed that CT genotype of SNP1 had a much lower T level than CC genotype (p<0.05) and the GSI of individuals with CC genotype of SNP2 was higher than those with TT genotype (p<0.05). Four diplotypes were constructed based on the two SNPs and the diplotype D3 had a significantly lower T level and GSI. In conclusion, the two SNPs were significantly associated with reproductive traits of Japanese flounder.

• 한국식품영양과학회지
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• 제26권4호
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• pp.675-681
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• 1997

체내에서 영양소의 흡수에 영향을 미치는 에탄올과 섬유소 및 단백질의 급여수준에 따른 이 들 상호작용을 구명하기 위해 에탄올을 투여한 횐쥐에게 단백질 급여 수준을 7%와 20%로 달리 하고 섬유소를 5%와 10% 첨가한 실험식이를 5주간 급여하므로써 이들 영양소가 에탄을 대사효소와 항산화 물질에 미치는 영향을 관찰하였다. Aldehyde dehydrogenase(ADH)와 microsomal ethanol oxidizing system(MEOS) 활성은 에탄을 투여시 대조군에 비해 유의적으로 증가하였으며, 특히 MEOS 활성은 단백질 정상 급여와 정상섬유소 급여시 그 증가가 현저하였다. 에탄을 투여로 감소된 aldehyde de-hydrogenase(AIDH) 활성은 정상섬유소군의 경우 단백질 적정 급여시 유의적인 감소를 나타내었다. Cytoch-rome P-450(P-450) 활성은 에탄을 투여로 증가되었으며 에탄을 투여군에서 단백질 정상급여와 과량의 섬유소 급여로 유의하게 감소되었다. Xanthine oxidase (XO) 활성은 에탄을 투여로 증가하는 경향이었으며, 저 단백군에 비하여 단백질 적정 급여시 유의적인 증가를 나타내었다. 또한 섬유소 급여수준에 따른 XO 활성은 에탄올 투여군 중 단백질 정상군에서만 유의적인 차이가 관찰되었다. 에탄을 투여는 간조직 중의 글루타티온 함량을 유의적으로 감소시켰으며, 단백질 결핍에 따른 영향이 현저하게 나타났다. 간조직 중의 지질과 산화 함량은 단백질 결핍시 에탄올 투여로 증가하였다. 이상의 결과에서 에탄올을 해독키 위하여 간의 ADH와 MEOS 활성이 증가되었으며 이로 인해 생성된 아세트알데히드는 AIDH 보다 XO를 통해 해독된 것으로 나타났다. 또한 에탄올 대사효소 활성에 요구되는 단백질 공급과 10% 즉, 과량의 섬유소 급여 보다 5% 섬유소 급여시 에탄올성 간손상을 경감시킬 수 있을 것으로 사료된다.