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Biomedical subjects

I Johansson

Publications and source records attributed to I Johansson.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.

The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of risperidone to its major active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), has been documented after single oral doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the steady-state plasma concentrations of risperidone and 9-OH-risperidone was investigated. Thirty-seven schizophrenic patients on monotherapy with risperidone, 4-8 mg/day, were genotyped by RFLP and PCR for the major functional variants of the CYP2D6 gene. Steady state plasma levels of risperidone and 9-OH-risperidone were analysed by HPLC. Based on the genotype analysis, three patients were classified as ultrarapid metabolizers (UM) with an extra functional CYP2D6 gene, 16 were homozygous extensive metabolizers (EM), 15 heterozygous EM and three poor metabolizers (PM). The median steady-state plasma concentration-to-dose (C/D) ratios of risperidone were 0.6, 1.1, 9.7 and 17.4 nmol/l per mg in UM, homozygous EM, heterozygous EM and PM, respectively, with statistically significant differences between PM and the other genotypes (P < 0.02). The C/D of 9-OH-risperidone also varied widely but was not related to the genotype. The risperidone/9-OH-risperidone ratio was strongly associated with the CYP2D6 genotype, with the highest ratios in PM (median 0.79). Heterozygous EM also had significantly higher ratios than homozygous EM (median value 0.23 versus 0.04; P < 0.01) or UM (median 0.03; P < 0.02). No significant differences were found in the C/D of the sum of the plasma concentrations of risperidone and 9-OH-risperidone between the genotype groups. In conclusion, the steady-state plasma concentrations of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotype. However, as risperidone and 9-OH-risperidone are considered to have similar pharmacological activity, the lack of relationship between the genotype and the sum of risperidone and 9-OH-risperidone indicates that the CYP2D6 polymorphism may be of limited importance for the clinical outcome of the treatment.

Adult↗
PubMed1999

Caring attributes, professional self concept and technological influences in a sample of Registered Nurses in eleven countries.

Caring, the theoretical foundation of nursing, is identified as one of the core values by Hospital Authorities world-wide to be actualised in clinical practice. Exactly how caring attributes relate to nurses' professional self image and quality nursing service in the context of a contemporary technological environment have yet to be operationalised. In total, 1957 Registered Nurses from 11 different countries were involved in the study which aimed to: develop an understanding of and compare the responses to items relating to caring, professional self concept and technological influences. To collect data an instrument containing 104 Likert items was administered to RNs working in general hospitals. The instrument contained sections which examined professional self concept, technological influences and caring attributes. Descriptive and inferential statistics revealed that many of the Asian nurses in the sample were younger, had less experience yet were more qualified than their 'western' colleagues. The mean scores for the caring attributes for nurses from the Philippines, Sweden and South Africa were significantly higher than those from China (Beijing), Korea, China (Hong Kong) and Scotland. The Korean sample demonstrated the lowest mean score for professional self concept while the New Zealand sample the highest. The Australian, Canadian, NZ, Scotland and Swedish samples were strongly of the opinion that the increase in technology has not brought about the any more spare time in nursing and generally had a more negative opinion about the influence of technology when compared to those from China (Beijing), Philippines, China (Hong Kong) and Singapore. The results are discussed in the light of the cultural differences in the sample and recommendations for future research are considered.

Adult↗
PubMed1999

Aquaporins and water homeostasis in plants.

Aquaporins are water channel proteins of vacuolar and plasma membranes. When opened they facilitate the passive movement of water molecules down a water potential gradient. In Arabidopsis, 30 genes have been found that code for aquaporin homologues. Some of these genes code for highly abundant constitutively expressed proteins and some are known to be temporally and spatially regulated during development and in response to stress. The water transport activity of two aquaporins is regulated at the protein level by phosphorylation and dephosphorylation. At a given time, cells express several different aquaporins, and it is probable that vacuolar and plasma membrane aquaporins acting in concert are responsible for the cytosolic osmoregulation that is necessary for maintaining normal metabolic processes. Inhibition studies of aquaporins in vivo and antisense mutant studies suggest that, in addition to cytosolic osmoregulation, aquaporins are important for the bulk flow of water in plants.

Journal Article↗
PubMed1999

Coronary risk factors, diet and vitamins as possible explanatory factors of the Swedish north-south gradient in coronary disease: a comparison between two MONICA centres.

OBJECTIVE: To investigate whether differences in serum lipids, diet, plasma vitamins or other risk factors explain the higher incidence of cardiovascular disease in the northern parts of Sweden, compared to Göteborg on the west coast. DESIGN: A comparison between the two Swedish MONICA populations in northern Sweden (NSW) and in Göteborg (GOT) in 1990. SETTING: Norrbotten and Västerbotten counties in the north of Sweden and the city of Göteborg on the west coast. SUBJECTS: In the north 1583 men and women aged 25-64 years were investigated, and in Göteborg 1574 men and women. Plasma vitamins were examined in a subsample of men aged 40-49 (n = 259). MAIN OUTCOME MEASURES: Serum lipids, blood pressure, anthropometric measurements, smoking habits, physical activity, diet, education, and plasma vitamins. RESULTS: NSW men and women had mean serum total cholesterol of 6.30 (standard deviation 1.23) mmol L-1 and 6.12 (1. 33) mmol L-1, compared to 5.75 (1.14) mmol L-1 and 5.67 (1.24) mmol L-1 in GOT men and women (P = 0.0001). NSW men and women were shorter and had higher body mass index than in Göteborg. Cigarette smoking was slightly more prevalent amongst GOT men and women. Göteborg men and women more often had more than compulsory school education, compared to NSW men and women, whereas there were no differences in physical activity during leisure time. There were no differences in vegetable consumption, whereas fruit was consumed more frequently by NSW women compared to GOT women, with a higher intake of fibre and ascorbate. Consumption of wine and total alcohol consumption were higher in Göteborg, whereas NSW men and women drank significantly more coffee. In the subsample of men (aged 40-49) who had plasma vitamins measured, men in Göteborg had slightly higher mean retinol concentrations (P = 0.005) and lutein and zeaxanthine levels (P = 0.006 and 0.009, respectively) compared to northern men, but there were no differences with respect to alpha- or beta-carotene, ascorbic acid or lipid-adjusted vitamin E. NSW men had slightly higher plasma iron and magnesium concentrations (P = 0.005 and 0.001, respectively). CONCLUSION: The largest and most consistent differences between Göteborg and northern Sweden were found for serum cholesterol, probably reflecting differences in intake of saturated fat. The differences in serum cholesterol may explain a substantial part of the differences in coronary heart disease morbidity and mortality. We found no consistent differences concerning vegetable and fruit consumption. More alcohol was consumed in Göteborg. Differences in education and childhood conditions, as reflected in differences in height, may contribute to the north-south gradient with respect to CHD incidence and mortality.

Adult↗
PubMed1999

Strains of Actinomyces naeslundii and Actinomyces viscosus exhibit structurally variant fimbrial subunit proteins and bind to different peptide motifs in salivary proteins.

Oral strains of Actinomyces spp. express type 1 fimbriae, which are composed of major FimP subunits, and bind preferentially to salivary acidic proline-rich proteins (APRPs) or to statherin. We have mapped genetic differences in the fimP subunit genes and the peptide recognition motifs within the host proteins associated with these differential binding specificities. The fimP genes were amplified by PCR from Actinomyces viscosus ATCC 19246, with preferential binding to statherin, and from Actinomyces naeslundii LY7, P-1-K, and B-1-K, with preferential binding to APRPs. The fimP gene from the statherin-binding strain 19246 is novel and has about 80% nucleotide and amino acid sequence identity to the highly conserved fimP genes of the APRP-binding strains (about 98 to 99% sequence identity). The novel FimP protein contains an amino-terminal signal peptide, randomly distributed single-amino-acid substitutions, and structurally different segments and ends with a cell wall-anchoring and a membrane-spanning region. When agarose beads with CNBr-linked host determinant-specific decapeptides were used, A. viscosus 19246 bound to the Thr42Phe43 terminus of statherin and A. naeslundii LY7 bound to the Pro149Gln150 termini of APRPs. Furthermore, while the APRP-binding A. naeslundii strains originate from the human mouth, A. viscosus strains isolated from the oral cavity of rat and hamster hosts showed preferential binding to statherin and contained the novel fimP gene. Thus, A. viscosus and A. naeslundii display structurally variant fimP genes whose protein products are likely to interact with different peptide motifs and to determine animal host tropism.

Actinomyces↗
PubMed1999

Decreased capacity for debrisoquine metabolism among black Tanzanians: analyses of the CYP2D6 genotype and phenotype.

The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate debrisoquine with 59% of the Tanzanian extensive metabolisers having debrisoquine metabolic ratios (MRs) > 1 versus 20% in Caucasians. This decrease in metabolic capacity was not fully explained by the partially or fully detrimental CYP2D6 gene mutations analysed for in this study. As many as 7% poor metabolizers of debrisoquine were identified but none was homozygous for defective CYP2D6 alleles. The majority among the group of poor metabolizers had relatively low metabolic ratios. The mutational profile indicated a closer association of the Tanzanian CYP2D locus to that of Zimbabweans rather than to that of Ethiopians. The defective alleles CYP2D6*3, *4, *5 and *6 were found at low frequencies (0%, 1%, 6%, 0%, respectively), whereas the CYP2D6*17 allele causing an enzyme with altered specificity was common (allele frequency = 17%). It is concluded that the CYP2D6 genotype in the Tanzanian Bantu population is different from that of other African populations examined to date and that further studies are required to explain the generally lower capacity to metabolize CYP2D6 substrates.

Base Sequence↗
PubMed1998

Enzyme histochemical and immunohistochemical localization of carbonic anhydrase as a marker of ductal differentiation in the developing rat parotid gland.

BACKGROUND: Carbonic anhydrase has been localized to the acini and ducts of mature rat parotid glands. This enzyme has been associated with ion transport, a prominent function of striated and excretory ducts in salivary glands, suggesting that it might be used as a marker of ductal differentiation. The purpose of this study was histochemically to document developmental changes in carbonic anhydrase in the ducts of the rat parotid gland. METHODS: Parotid glands were excised from rats at representative developmental ages. Enzyme histochemistry was done on frozen sections fixed in acetone, and immunohistochemistry was performed with antibodies to human carbonic anhydrase isoenzymes I, II, and VI on paraffin sections of glands fixed in Helly's fluid. RESULTS: Carbonic anhydrase activity was weak until age 21 days after birth, when it had increased slightly in the acini and intercalated ducts and moderately in striated and excretory ducts. The adult pattern was attained by 28 days, in which reactions were moderate to strong in the striated and excretory ducts and modest in the acini and intercalated ducts. Immunohistochemical reactions were weak until 14 days, then increased rapidly, and by 28 days approached the adult pattern of virtually none in the acini and modest to moderately strong in the striated and excretory ducts. The order of reaction intensity of the antibodies was II > I > VI. CONCLUSIONS: Carbonic anhydrase is a useful marker of the functional differentiation of the striated and excretory ducts of the developing rat parotid gland.

Animals↗
PubMed1998

Sense of coherence, quality of life, and function among elderly hip fracture patients.

The aim was to study whether sense of coherence (SOC) had any predictive power in patients with hip fractures regarding length of stay in hospital, state of confusion and health, functional ability, quality of life, and municipal home-help service. A total of 73 patients admitted from their own homes participated (mean age 80.4 years). The patients were followed during a 4-month period. Acute confusional state was diagnosed using a Swedish version of the NEECHAM Confusion Scale. SOC and self-rated functional health status were assessed during the hospitalization period and one month after discharge; Quality of Life Index (QLI) and instrumental daily activities (SPE) were assessed four months after discharge. Focusing on the differences in outcome between persons with a stronger vs a weaker SOC, there were few significant differences in physical status between the subgroups. However, the persons with a weaker SOC stayed longer in the hospital and reported a significantly lower score on the NEECHAM Confusion Scale, as well as more discomfort and disability symptoms related to communication, mental, and emotional status. Furthermore, these persons had less favorable scores on the overall QLI and subscales respectively, and on all subscales measuring instrumental daily activities. The persons with a weaker SOC were significantly more dependent on assistance before admission to the hospital than those with a stronger SOC. The conclusions drawn from the study indicate that persons with a stronger SOC seem to cope in a better way with their situation after a hip fracture.

Activities of Daily Living↗
PubMed1998

Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.

OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.

Administration, Oral↗
PubMed1998

Jaw lift--a simple and effective method to open the airway in children.

Assessment of breathing during resuscitation of children is important. Misjudgement due to failure to open the airway may lead to mouth-to-mouth ventilation in unconscious children who have retained spontaneous breathing efforts, and might lead to completely ineffective ventilation with gastric distension. The efficiency of the standard head tilt-chin lift manoeuvre (HT-CL) and the jaw lift manoeuvre (JL) for opening of the airway in children was investigated. Fifty children between 1 and 9 years of age breathing spontaneously during deep anaesthesia were studied. Both manoeuvres were randomly performed in all children by nurse anaesthetists. The time for opening and the quality of the airway was determined by a blind folded anaesthesiologist listening to the breathing sounds. The standard HT-CL manoeuvre was insufficient in 12% of the children. JL was more effective than HT-CL in opening the airway in unconscious children who had retained attempts at spontaneous breathing. The JL manoeuvre may, therefore, be recommended in situations when the HT-CL manoeuvre is insufficient.

Age Factors↗
PubMed1998

Activated transcription of the human neuropeptide Y gene in differentiating SH-SY5Y neuroblastoma cells is dependent on transcription factors AP-1, AP-2alpha, and NGFI.

Activated transcription of the human neuropeptide Y gene (NPY) was investigated in SH-SY5Y neuroblastoma cells at the onset of sympathetic neuronal differentiation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) and serum or by nerve growth factor (NGF). As determined by transient expression, two NGF response elements (REs) were required for transcription induced by NGF in SH-SY5Y cells with stable expression of an exogenous NGF receptor TRK-A gene (SH-SY5Y/trk). TPA treatment in the presence of serum induced NPY transcription in both wild-type SH-SY5Y (SH-SY5Y/wt) and SH-SY5Y/trk cells. A TPA RE (TRE), overlapping the proximal NGF RE, was identified by expression of the v-Jun oncoprotein that enhanced NPY transcription. Suppression of TPA-induced NPY transcription was obtained by expression of a dominant negative Jun protein, selective protein kinase C inhibition, or introduction of a mutated TRE, whereas NGF-induced NPY transcription was inhibited to a lesser degree. The transcription factor AP-2alpha was shown to bind cooperatively to the NPY promoter with either AP-1 or NGFI-A to the shared TRE and NGF RE and to the distal NGF RE, respectively. These results show that transcription factors AP-1, AP-2alpha, and NGFI-A are involved in activated NPY transcription during the onset of neuronal differentiation.

Base Sequence↗
PubMed1998

Water transport activity of the plasma membrane aquaporin PM28A is regulated by phosphorylation.

PM28A is a major intrinsic protein of the spinach leaf plasma membrane and the major phosphoprotein. Phosphorylation of PM28A is dependent in vivo on the apoplastic water potential and in vitro on submicromolar concentrations of Ca2+. Here, we demonstrate that PM28A is an aquaporin and that its water channel activity is regulated by phosphorylation. Wild-type and mutant forms of PM28A, in which putative phosphorylation sites had been knocked out, were expressed in Xenopus oocytes, and the resulting increase in osmotic water permeability was measured in the presence or absence of an inhibitor of protein kinases (K252a) or of an inhibitor of protein phosphatases (okadaic acid). The results indicate that the water channel activity of PM28A is regulated by phosphorylation of two serine residues, Ser-115 in the first cytoplasmic loop and Ser-274 in the C-terminal region. Labeling of spinach leaves with 32P-orthophosphate and subsequent sequencing of PM28A-derived peptides demonstrated that Ser-274 is phosphorylated in vivo, whereas phosphorylation of Ser-115, a residue conserved among all plant plasma membrane aquaporins, could not be demonstrated. This identifies Ser-274 of PM28A as the amino acid residue being phosphorylated in vivo in response to increasing apoplastic water potential and dephosphorylated in response to decreasing water potential. Taken together, our results suggest an active role for PM28A in maintaining cellular water balance.

Animals↗
PubMed1998

Duplex criteria for grading internal carotid artery stenosis > 50% based on multiregression analysis.

Different opinions exist about grading > 50% stenosis resulting from differences in angiographically estimated measurements and differences in weighing hemodynamic parameters at duplex scanning. The aim of this study was to reevaluate the correlation between duplex scanning measurements and angiographic findings in > 50% stenosis by using correlation coefficients instead of earlier determination coefficients in multiregression analysis in prediction of an absolute percentage of stenosis > or = 50%. The authors correlated the angiographic findings for 58 vessels with 50%-99% stenosis with findings at duplex examination. Peak systolic velocity (PSV) > 1.2 m/s was the limit for > 50% stenosis. The degree of stenosis was estimated as the smallest diameter of the diseased vessel divided by normal diameter of the vessel at the same level. Predictive values of different variables either alone or in combination were calculated by means of multiregression analysis. The highest predictive value was PSV, followed by late diastolic velocity (LDV) and pulse pressure (PSV-LDV) according to multiregression analysis. The results of Doppler evaluations of periorbital flow (POF) enhanced the differentiation between > 75% stenosis and < 75% stenosis. The combination of PSV and LDV and the result of POF coded as normal and abnormal had the highest accuracy in the prediction of absolute percentage of stenosis with a difference of 6.3 +/- 4.3% (SD) between the results of duplex scanning and angiography (r = 0.88). The accuracy in discriminating instances in which there was at least 75% reduction in luminal diameter was 98.2%. We found the quotient between PSV in the internal carotid artery and PSV in the common carotid artery to be less predictive with an accuracy of 84%. However, in the presence of severe stenosis in the external carotid artery, periorbital examination is not reliable. In such a situation it is preferable to use an equation based on pulse pressure and LDV. In prediction of > 50% stenosis we found multiregression analysis in the assessment of the predictive value of combined variables to be more accurate than single regression of each variable.

Aged↗
PubMed1998

Perindopril treatment affects both preglomerular renal vascular lumen dimensions and in vivo responsiveness to vasoconstrictors in spontaneously hypertensive rats.

We have previously shown that chronic treatment with angiotensin-converting enzyme inhibition (ACEI) did not reverse hypertrophy of the renal arterial wall in spontaneously hypertensive rats (SHR). In this study we determined the effects of perindopril on the functional properties of the renal vasculature in vivo and on its resistance to flow at maximal dilatation in vitro, a measure of vessel lumen diameter. Two groups of SHR were studied: untreated or treated with perindopril (3 mg/kg per day) in their drinking water from 4 weeks of age. At 10 weeks, (1) vessel lumen characteristics were assessed using a maximally dilated in vitro isolated kidney perfusion and (2) the renal vasoconstrictor responses to bolus doses of vasoactive agents (angiotensin II and phenylephrine) administered into the renal artery were measured in vivo (anesthetized rats). Mean arterial pressure was significantly lower in conscious SHR treated with perindopril (132+/-2 versus 97+/-2 mm Hg, P<.001). In vitro, the pressure-flow relationship and the pressure-glomerular filtration rate relationship were both shifted significantly to the left (P<.001). The perindopril-treated kidneys began filtering at a significantly lower threshold perfusion pressure than nontreated controls (P<.001). In vivo, renal vasoconstrictor responses to increasing doses of both vasoconstrictor agents were significantly less marked in the perindopril-treated SHR than in untreated SHR (P<.05). Thus, chronic ACEI increased average renal vessel lumen diameter in SHR, predominantly in preglomerular vessels, and reduced renal vasoconstrictor responsiveness in vivo, findings compatible with remodeling of the preglomerular vasculature around a greater lumen.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction.

CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes. In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

Alleles↗
PubMed1997

Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells.

We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1 and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OME did not bind specifically to AhR, and it could not activate the AhR complex in rat cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro. Genistein, a tyrosine kinase inhibitor, and daidzein, an inhibitor of casein kinase II, efficiently inhibited OME-mediated but not B(a)P- or TCDD-mediated induction of CYP1A1, as monitored at the transcriptional, mRNA, and protein levels as well as by analysis of activation of XRE-luciferase reporter constructs transfected into H4IIE cells. The protease inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and lavendustin A also had similar OME-specific effects. In addition, insulin pretreatment caused an almost complete inhibition of OME-dependent CYP1A1 induction but only partially affected TCDD and B(a)P-mediated induction of CYP1A1. Staurosporine, an inhibitor of protein kinase C, impaired the induction by both B(a)P and OME. OME caused an approximately 2-fold increase in the level of CYP3A expression, but all inhibitors used were ineffective in preventing this induction. Gel shift analysis with radiolabeled XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the AhR.Arnt complex into the nuclei. Genistein inhibited the specific nuclear XRE binding caused by OME, but it potentiated the formation of the TCDD-induced XRE.AhR complex. Although daidzein was able to effectively inhibit the OME-stimulated CYP1A1 gene transcription, it did not influence the OME-dependent AhR.XRE complex formation. The data are consistent with a mechanism for OME-mediated induction of CYP1A1 that involves activation of the AhR complex via intracellular signal transduction systems and that is distinct from induction mediated by AhR ligands.

Animals↗