Biomedical subjects

Yuji Ishii

Publications and source records attributed to Yuji Ishii.

At least 19 recordsLinked to original sources

PubMed2006

In vivo mutagenicity and initiation following oxidative DNA lesion in the kidneys of rats given potassium bromate.

To clarify the role of 8-OHdG formation as a starting point for carcinogenesis, we examined the dose-dependence and time-course of changes of OGG1 mRNA expression, 8-OHdG levels and in vivo mutations in the kidneys of gpt delta rats given KBrO3 in their drinking water for 13 weeks. There were no remarkable changes in OGG1 mRNA in spite of some increments being statistically significant. Increases of 8-OHdG occurred after 1 week at 500 p.p.m. and after 13 weeks at 250 p.p.m. Elevation of Spi- mutant frequency, suggestive of deletion mutations, occurred after 9 weeks at 500 p.p.m. In a two-stage experiment, F344 rats were given KBrO3 for 13 weeks then, after a 2-week recovery, treated with 1% NTA in the diet for 39 weeks. The incidence and multiplicity of renal preneoplastic lesions in rats given KBrO3 at 500 p.p.m. followed by NTA treatment were significantly higher than in rats treated with NTA alone. Results suggest that a certain period of time might be required for 8-OHdG to cause permanent mutations. The two-step experiment shows that cells exposed to the alteration of the intranuclear status by oxidative stress including 8-OHdG formation might be able to form tumors with appropriate promotion.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Lack of in vivo mutagenicity and oxidative DNA damage by flumequine in the livers of gpt delta mice.

Flumequine (FLU), an anti-bacterial quinolone agent, has been recognized as a non-genotoxic carcinogen for the mouse liver, but recent reports have suggested that some genotoxic mechanism involving oxidative DNA damage may be responsible for its hepatocarcinogenesis. In the present study, we investigated this possibility in the mouse liver using male and female B6C3F1 gpt delta mice fed diet containing 0.4% FLU, a carcinogenic dose, for 13 weeks. Measurements of 8-hydroxydeoxyguanosine levels in liver DNA, and gpt point and deletion mutations revealed no significant increases in any of these parameters in either sex. Histopathologically, centrilobular swelling of hepatocytes with vacuolation was apparent, however, together with significant increase in bromodeoxyuridine-labeling indices in the treated males and females. These results suggest that genotoxicity, including oxidative DNA damage, is not involved in mouse hepatocarcinogenesis by FLU, which might rather solely exert tumor-promoting effects in the liver.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Fatty acyl-CoA as an endogenous activator of UDP-glucuronosyltransferases.

The acyl-CoA-dependent modulation of hepatic microsomal UDP-glucuronosyltransferase (UGT) function in rats was studied. Oleoyl- and palmitoyl-CoAs inhibited UGT activity toward 4-methylumbelliferone in the presence of Brij 58. However, acyl-CoAs enhanced UGT activity in untreated microsomes. A maximum activation of about 8-fold over the control was observed at 15 microM oleoyl-CoA, whereas 50 microM or more oleoyl-CoA had an inhibitory effect on UGT function. Medium- and long-chain acyl-CoAs also exhibited similar effects. On the basis of resistance to tryptic digestion of UGTs, oleoyl-CoA at 15 microM has no ability to change the permeability of the endoplasmic reticulum (ER) membrane, although perturbation of the membrane occurred with 50 microM oleoyl-CoA. N-Ethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic acid) abolished the oleoyl-CoA (15 microM)-dependent activation of microsomal UGT. These results suggest that: (1) acyl-CoAs play a role as an endogenous activator of UGTs, and (2) a sulfhydryl group is required for the activation of UGT by physiological concentrations of acyl-CoAs.

Acyl Coenzyme A↗

PubMed2006

Inhibition of UDP-glucuronosyltransferase 2b7-catalyzed morphine glucuronidation by ketoconazole: dual mechanisms involving a novel noncompetitive mode.

Glucuronidation of morphine in humans is predominantly catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). Since our recent research suggested that cytochrome P450s (P450s) interact with UGT2B7 to affect its function [Takeda S et al. (2005) Mol Pharmacol 67:665-672], P450 inhibitors are expected to modulate UGT2B7-catalyzed activity. To address this issue, we investigated the effects of P450 inhibitors (cimetidine, sulfaphenazole, erythromycin, nifedipine, and ketoconazole) on the UGT2B7-catalyzed formation of morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G). Among the inhibitors tested, ketoconazole was the most potent inhibitor of both M-3-G and M-6-G formation by human liver microsomes. The others were less effective except that nifedipine exhibited an inhibitory effect on M-6-G formation comparable to that by ketoconazole. Neither addition of NADPH nor solubilization of liver microsomes affected the ability of ketoconazole to inhibit morphine glucuronidation. In addition, ketoconazole had an ability to inhibit morphine UGT activity of recombinant UGT2B7 freed from P450. Kinetic analysis suggested that the ketoconazole-produced inhibition of morphine glucuronidation involves a mixed-type mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. In contrast, addition of another substrate, testosterone, showed no or a minor effect on ketoconazole-produced inhibition of morphine UGT. These results suggest that 1) metabolism of ketoconazole by P450 is not required for inhibition of UGT2B7-catalyzed morphine glucuronidation; and 2) this drug exerts its inhibitory effect on morphine UGT by novel mechanisms involving competitive and noncompetitive inhibition.

Analgesics, Opioid↗

PubMed2006

Determination of nitrotyrosine and tyrosine by high-performance liquid chromatography with tandem mass spectrometry and immunohistochemical analysis in livers of mice administered acetaminophen.

Nitrotyrosine (NTYR) is used as a biomarker of nitrative pathology caused by peroxynitrite (ONOO-) formation. NTYR measurement in biological materials usually employs such methodologies as immunohistochemistry staining, high-performance liquid chromatography and gas chromatography. In this study, we developed a method for the determination of tyrosine (TYR) and NTYR, using liquid chromatography with tandem mass spectrometry (LC-MS/MS). In order to confirm the applicability of our method to an in vivo system, we measured protein-bound NTYR levels using by LC-MS/MS method and immunohistochemical analysis in liver of B6C3F1 mice at 2 h, 4 h and 8 h after administration of 300 mg/kg acetaminophen (APAP). A mass spectrometer equipped with an electrospray ionization source using a crossflow counter electrode and ran in the positive ion mode (ESI+) was set up for multiple reaction monitoring (MRM), which monitored the transitions 182.2>136.2, 227.1>181.2, 191.3>144.4 and 236.3>189.5, for TYR, NTYR, [13C9]-TYR and [13C9]-NTYR, respectively. The average recoveries from mice liver protein samples spiked with 25 microM TYR and 100 nM NTYR were 94.4% and 95.6%, respectively, with correction using the added surrogate standards. The limits of quantification were 100 nM for TYR and 0.5 nM for NTYR. NTYR was detected all liver samples of mice by the proposed LC-MS/MS method. The concentration range of NTYR per milligram protein in samples was 0.17-0.3 pmol/mg protein. And the level reached a maximum at 4 h. These data were well correlated with the result obtained by an immunohistochemical reaction with anti-NTYR antibody. The LC-MS/MS method was able to determine protein-bound NTYR in a small amount of tissue sample, and is therefore expected to be a very powerful tool for evaluating ONOO- generation in an in vivo system.

Acetaminophen↗

PubMed2006

Possible involvement of NO-mediated oxidative stress in induction of rat forestomach damage and cell proliferation by combined treatment with catechol and sodium nitrite.

To clarify the mechanisms underlying forestomach carcinogenesis in rats by co-treatment with catechol and sodium nitrite (NaNO2), we investigated the involvement of oxidative stress resulting from reaction of the two compounds. Since generation of semiquinone radical, hydroxyl radical (*OH), and peroxynitrite (ONOO-) arose through the reaction of catechol with NO, we proposed that superoxide resulting from catechol oxidation reacted with excess NO, consequently yielding *OH via ONOO-. Male F344 rats were co-treated with 0.2% catechol in the diet and 0.8% NaNO2 in the drinking water for 2 weeks. Prior to occurrence of histological evidence indicating epithelial injury and hyperplasia, 8-hydroxydeoxyguanosine levels in forestomach epithelium significantly increased from 12 h together with appearance of immunohistochemically nitrotyrosine-positive epithelial cells. There were no remarkable changes in rats given each chemical alone. We conclude that oxidative stress due to NO plays an important role in induction of forestomach epithelial damage, cell proliferation, and thus presumably forestomach carcinogenesis.

Administration, Oral↗

PubMed2006

Nine-week detection of six genotoxic lung carcinogens using the rasH2/BHT mouse model.

A 9-week in vivo rasH2/butylhydroxytoluene (BHT) model for the detection of genotoxic lung carcinogens was validated, using six potent positive test compounds, dimethylnitrosamine (DMN; 15 mg/kg, i.p.), diethylnitrosamine (DEN; 100 mg/kg, i.p.), ethylnitrosourea (ENU; 120 mg/kg, i.p.), 3-methylcholanthrene (MC; 100 mg/kg, i.p.), 7,12-dimethylbenz(a)anthracene (DMBA; 5 mg/kg, i.g.) and benzo(a)pyrene (B(a)P; 80 mg/kg, i.p.), each given to rasH2 mice of both genders by single administration for initiation followed by promoter BHT treatment. Statistically significant increase in the incidence and multiplicity of lung tumors was observed in rasH2 mice treated with BHT following exposure to all of the carcinogens tested. The data overall suggest the rasH2/BHT model to be a powerful screening tool for genotoxic lung carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2006

Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters.

Potential chemopreventive effects of naturally occurring agents were investigated using a new 16-week medium-term pancreatic carcinogenesis models in hamsters. Male 6-week-old Syrian hamsters were subcutaneously injected with 10mg/kg body weight N-nitrosobis(2-oxopropyl)amine (BOP) four times within a week, and fed a diet supplemented with 80ppm benzyl isothiocyanate (BITC), 80ppm sulforaphane (SFN) or 10ppm resveratrol (RES) during the initiation or post-initiation stages. For the initiation stage, each chemical was given for 3 weeks including 1 week before and after the BOP injections. With post-initiation exposure, the groups were changed from basal diet 1 week after the last BOP injection, and then fed each chemical for 14 weeks. All the animals were sacrificed after 16 weeks. The multiplicities of combined pancreatic lesions including atypical hyperplasias and adenocarcinomas were significantly decreased by BITC and SFN given in the initiation but not the post-initiation stage. On the other hand, RES, a naturally occurring inhibitor of cyclooxygenase-2 (COX-2) reported chemopreventive effects, failed to show significant effects on pancreatic carcinogenesis in either the initiation or post-initiation stages. Our data suggest that the naturally occurring isothiocyanates BITC and SFN can block BOP-initiation of hamster pancreatic carcinogenesis.

Adenocarcinoma↗

PubMed2006

Analysis of bile duct injuries (Stewart-Way classification) during laparoscopic cholecystectomy.

In order to investigate mechanisms underlying the occurrence of bile duct injuries (BDIs) during laparoscopic cholecystectomy (LC), we analyzed results for 34 patients (0.59%; 17 men, 17 women; average age, 57 years) with BDI out of 5750 LCs, based on questionnaire responses from surgical operators, records of direct interviews with these operators, operative reports, and videotapes of the operations. The indications for LC in the 34 patients were chronic cholecystitis in 32 patients and acute cholecystitis in 2. The BDIs in these patients were divided into four classes using the Stewart-Way classification: class I, incision (incomplete transection) of the common bile duct (CBD), n = 6 (17.6%); class II, lateral damage to the common hepatic duct (CHD), n = 9 (26.5%); class III, transection of the CBD or CHD, n = 15 (44.1%); and class IV, right hepatic duct or right segmental hepatic duct injuries, n = 4 (11.8%). In all class III and 3 class I cases (18 in total; incidence 53%), the mistake involved misidentifying the CBD as the cystic duct. Of all types (classes) of injuries, class III injuries showed the mildest gallbladder inflammation, and there was a significant (P = 0.0005) difference in the severity of inflammation between class II and III injuries. We conclude that complete transection of the CBD, which is rare in laparotomy, was the most common BDI pattern occurring during LC and that the underlying factor in the operator making this error was mistaking the CBD for the cystic duct.

Acute Disease↗

PubMed2006

Dose-dependent promotion of rat forestomach carcinogenesis by combined treatment with sodium nitrite and ascorbic acid after initiation with N-methyl-N'-nitro-N-nitrosoguanidine: possible contribution of nitric oxide-associated oxidative DNA damage.

Dose-dependent promotion effects of combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) on gastric carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Groups of 15 6-week-old F344 male rats were given 0.01% MNNG in their drinking water for 10 weeks to initiate carcinogenesis in the glandular stomach and a single intragastric administration of 100 mg/kg/bodyweight of MNNG by stomach tube at week 9 to initiate carcinogenesis in the forestomach. From week 11, they received either drinking water containing 0.05, 0.1 or 0.2% NaNO2 and a diet supplemented with 0.1 or 0.2% AsA in combination, each individual chemical alone or a basal diet until the end of week 42. In the forestomach, the incidence of hyperplasia was increased dose dependently by the treatment with NaNO2 alone. Incidences of neoplastic lesions were dramatically increased by the combined treatment with NaNO2 and AsA in a dose-dependent manner, but AsA itself had no effect. In the glandular stomach, only toxicity and regenerative changes were increased by the high-dose combination. In a second short-term experiment conducted for sequential observation, necrosis and strong inflammation were found in the forestomach epithelium shortly after commencing combined treatment with 1.0% AsA and 0.2% NaNO2, followed by hyperplasia, whereas there were no obvious effects in the glandular stomach. In addition, after a 4 h treatment with 1.0% AsA and 0.2% NaNO2, a slight increase in the 8-hydroxy-deoxyguanosine levels in the forestomach epithelium was observed by high-performance liquid chromatography and an electrochemical detection system, albeit without statistical significance. In vitro, electron spin resonance demonstrated nitric oxide formation during incubation with NaNO2 and AsA under acidic conditions. Thus, NaNO2 was demonstrated to exert promoter action in the forestomach, with AsA acting as a strong copromoter through cytotoxicity and regenerative cell proliferation, possibly mediated by oxidative DNA damage, but the combined treatment with NaNO2 and AsA had little influence on glandular stomach carcinogenesis.

Animals↗

PubMed2006

Lung as a new target in rats of 2-amino-3-methylimidazo[4,5-f]quinoline carcinogenesis: results of a two-stage model initiated with N-bis(2-hydroxypropyl)nitrosamine.

The effects of IQ on the promotion stage of DHPN-induced lung carcinogenesis and contributions of oxidative stress were investigated in rats. Groups of 20 male 6-week-old F344 rats were given 0.1% DHPN in their drinking water for 2 weeks for initiation. From the age of 9 weeks, they were treated with 0, 150 and 300 p.p.m. of IQ in the diet for 27 weeks. Control rats were similarly fed 300 p.p.m. IQ or basal diet alone without the preceding initiation. IQ clearly (P < 0.01) enhanced the multiplicity of lung tumors in a dose-dependent manner (DHPN alone, 3.63 +/- 1.80; DHPN +150 p.p.m. IQ, 11.50 +/- 5.04; DHPN +300 p.p.m. IQ, 18.83 +/- 4.58 [no./rat]). In addition, the incidence of lung tumors in the 300 p.p.m. IQ alone group (25%) was significantly (P < 0.05) higher than that in the non-treatment group (0%). In a second experiment, male rats were given IQ at doses of 0 and 300 p.p.m. in the diet for one week in order to analyze 8-OHdG formation, levels of TBARS and BrdU-LI in the lungs. There were no changes in 8-OHdG or TBARS levels, but significant elevation of BrdU-LI occurred in the IQ administration group. The overall data clearly indicate that IQ is a potent lung carcinogen in rats, in which oxidative stress may not be involved in lung carcinogenesis.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Induction of the hepatic cytochrome P450 2B subfamily by xenobiotics: research history, evolutionary aspect, relation to tumorigenesis, and mechanism.

The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not fully understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have not yet been answered. It is a puzzle that many structurally-unrelated chemicals can increase the expression of the CYP2B subfamily. This may support a mechanism(s) distinct from the signaling induced by ligand-receptor binding. Indeed, phenobarbital, a typical inducer, cannot associate with CAR. Thus, no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.

Animals↗

PubMed2005

A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol.

Our goal was to elucidate roles of Nrf2 in in vivo defense against pentachlorophenol (PCP), an environmental pollutant and hepatocarcinogen in mice. We examined oxidative stress and cell proliferation, along with other hepatotoxicological parameters, in the livers of nrf2-deficient (wild:+/+, heterozygous:+/-, homozygous:-/-) animals fed PCP in their diet at doses of 0, 150, 300, 600, or 1200 ppm for 4 weeks. For measurement of methoxyresorufin-O-demethylase (CYP 1A2), NAD(P):quinone oxidoreductase 1 (NQO1), and UDP-glucuronosyltransferase (UDP-GT), an additional study was performed with all but the 150-ppm dose. Significant elevation of 8-hydroxydeoxyguanosine (8-OH-dG) levels in the liver DNA was observed only in -/- mice treated with PCP at 1200 ppm. Levels of thiobarbituric-acid-reactive substances (TBARS) were also raised significantly compared to those of the relevant +/+ mice. Bromodeoxyuridine labeling indices (BrdU-LIs) of hepatocytes in -/- mice were significantly higher at all doses than those in the relevant +/+ mice. Relative liver weights were unchanged in mice lacking Nrf2, whereas liver weight in +/+ and +/- mice was increased. Significant elevations of serum ALP activity, but not ALT and AST activity, occurred at 600 ppm and above in -/- mice compared to the relevant +/+ mice. Histopathologically, centrilobular hepatocyte necrosis was severe in the -/- mice that received 600 ppm. Although CYP 1A2 activity was elevated in all treated mice, increases in NQO1 levels and UDP-GT activities did not occur only in -/- mice. These data suggest that Nrf2 plays a key role in prevention of PCP-induced oxidative stress and cell proliferation.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats.

Reproductive and developmental disorders are the most sensitive toxic effects caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is thought to produce many, if not all, of these toxic effects by impairing steroidogenesis and/or steroid action during the prenatal or early postnatal stages. However, the mechanism of the antisex steroid effect of TCDD is not well understood. This study revealed that steroidogenic acute-regulatory protein (StAR), a key transporter of cholesterol for steroidogenesis, in the testes of fetal rats are down-regulated by maternal exposure to TCDD. It was also shown that many mRNAs of steroidogenetic enzymes, including cytochromes P450 11A1, 17, and 11B1 and 3beta-hydroxysteroid dehydrogenase, are reduced in fetuses of TCDD-treated dams in a testis-specific manner. The same was also observed for the expression of estrogen-alpha receptors and androgen receptors. Whereas StAR expression was not affected by TCDD in cultured fetal testis, the fetal serum content of LH, a pituitary regulator of StAR, was significantly reduced by TCDD. In agreement with this, pituitary expression of LHbeta subunit mRNA in fetuses was reduced by maternal exposure to TCDD, whereas the alpha-subunit remained unchanged. The reduction in LHbeta is suggested to occur by a mechanism different from the reduction in the GnRH level. Direct supply of exogenous gonadotropin to TCDD-exposed fetuses completely abolished the reduction of StAR expression. Taken together, these results demonstrate that TCDD impairs steroidogenesis in the fetus by targeting pituitary gonadotropins.

Animals↗

PubMed2005

Induction of colon tumors in C57BL/6J mice fed MeIQx, IQ, or PhIP followed by dextran sulfate sodium treatment.

Heterocyclic amines (HCAs) have been shown to induce tumors in several organs of rodents, but except for MeIQ and PhIP, other HCAs such as MeIQx and IQ consistently failed to induce colon tumors in mice, whereas MeIQ, IQ, and PhIP exerted colon tumorigenicity in rats. Recently, we found that dietary MeIQx induces genotoxicity in the colon as well as the liver of two different types of reporter gene transgenic mice at subcarcinogenic doses such as 300 ppm. However, in the present study, dietary MeIQx did not significantly induce any tumors in C57BL/6J mice or gpt delta mice even when fed at 300 ppm for 78 weeks, suggesting that the treatment of MeIQx alone was not sufficient to promote colon tumors. In order to clarify a possibility whether such HCAs can induce colon tumors, C57BL/6J mice were fed MeIQx, IQ, or PhIP at a dose of 300 ppm for 12 weeks and, thereafter, twice received 1-week treatment with dextran sulfate sodium (DSS), 2 weeks apart. After 20 weeks, colon tumors including adenocarcinomas were found at incidences of 22%, 24%, and 45% in the groups receiving MeIQx, IQ, and PhIP, respectively, which were significantly (p < 0.05 or 0.01) different from the DSS alone value (0%). Thus our results clearly indicate that, in addition to PhIP, MeIQx and IQ can induce colon tumors in mice under an experimental condition promoting colon tumors.

Adenocarcinoma↗

PubMed2005

Functional protein-protein interaction of drug metabolizing enzymes.

Cytochrome P450 (P450, CYP), a major class of enzymes involved in Phase I drug metabolism, is expressed in the cellular endoplasmic reticulum together with other enzymes, such as microsomal epoxide hydrolase (mEH) and UDP-glucuronosyltransferase (UGT). In many cases, the metabolite produced by P450 is sequentially metabolized by other enzymes to increase its water solubility. It would be reasonable to assume that the metabolite produced by P450 is directly transferred to the other enzymes participating in its subsequent metabolism via protein-protein interactions for rapid metabolism. However, these steps have been considered to take place individually. Previously, we suggested that CYP1A1 specifically associates with mEH, UGTs and NADPH-P450 reductase. This observation strongly supports the view that there is functional cooperation between P450 and mEH/UGT to facilitate multistep drug metabolism. In recent years, accumulating evidence suggests the interaction between drug metabolizing enzymes and a change in enzymatic function by this interaction. In this review, we summarize the interaction between drug metabolizing enzymes and discuss its impact on their function.

Animals↗

PubMed2005

Suppression of carbonic anhydrase III mRNA level by an aryl hydrocarbon receptor ligand in primary cultured hepatocytes of rat.

The effect of an aryl hydrocarbon receptor (AhR) ligand on the carbonic anhydrase III (CAIII) mRNA level was studied using primary cultured hepatocytes of rats. CAIII gene which is highly suppressible by dioxins in vivo, was also suppressible in primary cultured hepatocytes of rats by an AhR ligand, 3-methylchlanthrene (3MC). The suppression of CAIII by 3MC was observed in a dose-dependent fashion. The suppression was marked at 10 microM MC. It is likely that AhR is involved in the suppression of the CAIII gene. The transcriptional regulation region of rat CAIII gene was cloned by polymerase chain reaction on the basis of the similarity to the mouse and human CAIII genes. A 1.5 kb section upstream of rat CAIII was sequenced and the transcription initiation site of this gene was mapped to 58 bases upstream of the initiation codon. A xenobiotic responsive element (XRE)-like sequence was found at -555 to -549 bp of the transcription initiation site. The location of XRE-like element was conserved between rats and mice those CAIIIs in liver were shown as dioxins-suppressible. Although the roles of the XRE have not been clarified, these results suggest that the AhR ligands could elicit the suppressive effect on hepatic CAIII and the effect on the factors from extrahepatic tissues is not required for the suppression.

Animals↗

PubMed2005

Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4.

Effects of cytochrome P450 isoforms, CYP1A2, CYP2C9 and CYP3A4, on the catalytic activity of UDP-glucuronosyltransferase 2B7 (UGT2B7) expressed in COS cell microsomal membranes were investigated using morphine as a substrate. When detergent-untreated COS cell microsomes were used as the enzyme source, the activity of morphine-3-glucuronide formation by UGT2B7 was reduced by addition of purified CYP1A2 and CYP2C9 in a concentration-dependent manner. The effect of CYP1A2 was greater than that of CYP2C9. In contrast, exogenous CYP3A4 had little effect on morphine glucuronidation activity. These results suggest that CYP1A2 and CYP2C9 have ability to modify UGT2B7 function. However, the mechanism(s) underlying the modulation of UGT2B7 function by these P450s seems to differ from that by CYP3A4.

Animals↗