Biomedical subjects

J L Zhu

Publications and source records attributed to J L Zhu.

At least 19 recordsLinked to original sources

PubMed2006

Laboratory work and pregnancy outcomes: a study within the National Birth Cohort in Denmark.

AIMS: To examine pregnancy outcomes in women doing laboratory work. METHODS: Using data from the Danish National Birth Cohort (1997-2003), the authors conducted a prospective cohort study of 1025 female laboratory technicians and 8037 female teachers (as reference). The laboratory technicians were asked about laboratory work tasks during pregnancy in an interview (at around 16 weeks of gestation). Pregnancy outcomes were obtained by linking the cohort to the national registers. Hazard ratios (HRs) of late fetal loss and diagnosing of congenital malformations were calculated by using Cox regression, and odds ratios (ORs) of preterm birth and small for gestational age were calculated by using logistic regression. RESULTS: Overall, there were no significant differences in pregnancy outcomes between laboratory technicians and teachers. However, we found that laboratory technicians working with radioimmunoassay or radiolabelling had an increased risk of preterm birth (OR = 2.2, 95% CI 0.8 to 6.2 for radioimmunoassay, and OR = 1.9, 95% CI 0.8 to 4.6 for radiolabelling) and "major" malformations (HR = 2.1, 95% CI 1.0 to 4.7 for radioimmunoassay, and HR = 1.8, 95% CI 0.9 to 3.7 for radiolabelling). The ORs of preterm birth doubled for women working with these tasks every day or several times a week. When an exposure matrix was applied, an increased risk of "major" malformations for exposure to organic solvents was seen. CONCLUSIONS: The results did not indicate any high risk of reproductive failures in laboratory technicians in general. Exposure to radioisotopes may carry a high risk of preterm birth and congenital malformations. This finding deserves further investigation.

Adult↗

PubMed2003

Shift work and subfecundity: a causal link or an artefact?

AIMS: The Danish National Birth Cohort (DNBC) was used to examine whether shift work is associated with reduced fecundity as estimated by time to pregnancy (TTP). METHODS: From 1 March 1998 to 1 May 2000, 39 913 pregnant women were enrolled in the DNBC. Data on job characteristics and TTP (0-2, 3-5, 6-12, and >12 months) were used for 17 531 daytime workers and 3907 shift workers who had planned the pregnancy. Fecundity odds ratios (ORs) were calculated with 95% confidence intervals using the discrete time survival analysis techniques performed by logistic regression. An OR above 1 expresses a shorter TTP and then a higher fecundity. Potential confounders, such as age at conception, gravidity, prepregnant body mass index, smoking, and alcohol consumption, as well as occupational characteristics, were also included in the model. RESULTS: Fixed evening workers and fixed night workers had a longer TTP. Compared with daytime workers, the adjusted ORs were 0.80 (95% CI 0.70 to 0.92) for fixed evening workers, 0.80 (95% CI 0.63 to 1.00) for fixed night workers, 0.99 (95% CI 0.91 to 1.07) for rotating shift (without night) workers, and 1.05 (95% CI 0.97 to 1.14) for rotating shift (with night) workers. When analysis was restricted to nulliparous women, the estimates remained unchanged. The proportions of unplanned pregnancies and contraceptive failures were higher among fixed evening and fixed night workers. CONCLUSIONS: There was no unequivocal evidence of a causal association between shift work and subfecundity. The slightly reduced fecundity among fixed evening workers and fixed night workers may be mediated by pregnancy planning bias or differential options for sexual contacts.

Circadian Rhythm↗

PubMed2002

Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark.

To investigate whether parents of children with congenital malformations more often developed cancer after birth of the child, a population-based case-control study in Denmark was undertaken. By linking the Cancer Registry with the Central Population Registry, we identified 8783 cancer patients having their first child born between 1977 and 1995 before the cancer was diagnosed. Parents of 41 206 firstborn children of a 10% random sample of newborns from the Birth Registry between 1980 and 1995 were identified as controls. We obtained malformation diagnoses of children of cases and controls by linking to the Hospital Discharge Registry. We estimated the association between malformation and cancer by using logistic regression, adjusting for maternal age at birth and sex of child. We found no increased risk of cancer in parents having children with malformations in general, but a higher cancer risk in parents of children born with cleft lip/palate, odds ratio (OR) for all cancer=1.8 (95% confidence interval 1.0-3.2), OR for lymphomas=4.2 (1.3-13.5) and OR for leukaemia=8.1 (2.0-33.7). This association was not restricted to cancer cases diagnosed shortly after birth of the child. Our results suggest a common genetic association between these diseases, but further studies are needed.

Adult↗

PubMed2001

Insulin-responsive nuclear proteins facilitate Sp1 interactions with the insulin-like growth factor-I gene.

The diabetes-induced decrease in insulin-like growth factor-I transcription appears to be mediated by footprint region V in exon 1. Since region V contains both an Sp1 site and an AT-rich element that recognizes an insulin-responsive binding protein (IRBP), we tested the hypothesis that Sp1 interactions are facilitated by an IRBP. Binding of nuclear extracts to region V probes was reduced by mutational or chemical interference with the AT-rich element. Blocking the AT site also reduced interactions of Sp1 with region V in vitro and blunted transactivation of region V reporter constructs by Sp1 in vivo. Sp1 binding was enhanced by small quantities of hepatic nuclear extracts, but enhancement was reduced by the AT mutation and abolished by a 5-base pair insertion between the AT-rich and GC-rich sites, and transactivation by Sp1 in vivo was diminished by inserting bases between the AT-rich and GC-rich elements. However, treating cells with insulin increased the ability of nuclear extracts to enhance Sp1 binding. These findings indicate that the presence of the AT-rich element is essential for the actions of Sp1 in vitro and in vivo, and the combination of both spacing requirements and insulin responsiveness suggests that IRBP may interact directly with Sp1.

AT Rich Sequence↗

PubMed2001

[Relationship between protein loss and dialysis duration results of PET and KT/Vurea in CAPD patients].

The study focused on the relationship between protein loss and dialysis duration, results of PET and KT/Vurea in two groups of CAPD patients. 16 patients of one group were included in CAPD for only 30 days while 19 patients of the other group were included in CAPD for more than one year. The results showed that value of protein loss had no obvious significance between both groups. Compared with the patients with value of PET D/Pcr < 0.65, the patients with value of PET D/Pcr > or = 0.65 had no significant protein loss. Between the patients whose index of urea clearance > or = 2.0, and those index of uera clearance < 2.0 the protein loss had no difference. It is suggested that, in routine dialysis duration peritoneal transport of small solutes and dialysis adequency. The conclusion shows furtherly that transportion of large protein and small solutes through different ways.

Adult↗

PubMed2001

Physiological concentrations of insulin promote binding of nuclear proteins to the insulin-like growth factor I gene.

Limitations in understanding the mechanism of transcriptional regulation by insulin are due in part to lack of models in which there is insulin-responsive binding of nuclear factors to critical promoter regions. The insulin-like growth factor I (IGF-I) gene responds to diabetes status via a footprinted sequence, region V, which contains an AT-rich element and a GC-rich site. We tested the hypothesis that insulin regulates nuclear factor binding to the AT-rich site. Gel shift analysis with liver nuclear extracts and a region V probe showed binding of Sp1, Sp3, and B(1), which persisted despite the presence of antibodies against Sp1 and Sp3. B(1) was detected by a probe mutated in the GC-rich site (VmSp1), but not by a probe mutated at the AT-rich site (VmAT). We then asked whether B(1) was responsive to insulin. For both region V and VmSp1 probes, nuclear extracts from normal rat hepatocytes, H4IIE cells, and CHO-IR cells exposed to 10(-6) M insulin exhibited an increase in binding, designated insulin-responsive binding protein (IRBP); IRBP comigrated with B(1) from liver extracts. IRBP binding to region V was competed by VmSp1, but not by VmAT, indicating specific interactions with the AT-rich sequence; insulin response elements from other genes also failed to compete. After addition of insulin, IRBP began to increase by 1 h and rose further at 24 h, suggesting involvement of both posttranslational and transcriptional mechanisms. IRBP responded to as little as 10(-10) M insulin, indicating physiological relevance. Induction of IRBP was blunted by the phosphatidylinositol 3'-kinase inhibitor LY294002, whereas other signal transduction inhibitors had little effect. IRBP interacts with an important sequence in the IGF-I gene and may participate in the metabolic regulation of IGF-I expression. As most insulin-responsive genes do not exhibit insulin-responsive nuclear factor binding, further studies of IRBP may also contribute to understanding of the mechanism of insulin action on gene transcription.

Animals↗

PubMed2000

Roles of tissue transglutaminase in ethanol-induced inhibition of hepatocyte proliferation and alpha 1-adrenergic signal transduction.

The mechanisms by which ethanol inhibits hepatocyte proliferation have been a source of some considerable investigation. Our studies have suggested a possible role for tissue transglutaminase (tTG) in this process. Others have shown that tTG has two distinctly different functions: it catalyzes protein cross-linking, which can lead to apoptosis and enhancement of extracellular matrix stability, and it can function as a G protein (Galpha(h)). Under that circumstance, we speculated that the cross-linking activity would be decreased and that it would function to enhance hepatocyte proliferation in response to adrenergic stimulation. Ethanol treatment inhibited hepatocyte proliferation and led to enhanced tTG cross-linking activity, whereas treatment of hepatocytes with an alpha1 adrenergic agonist, phenylephrine, enhanced hepatocyte proliferation while decreasing tTG cross-linking. However, phenylephrine treatment of several hepatoma cell lines had no effect on cellular proliferation or tTG cross-linking activity, and of note, Northern blot analysis demonstrated that whereas primary hepatocytes had high levels of the alpha1beta adrenergic receptor (alpha1BAR) mRNA, the hepatoma cell lines did not have this mRNA. When the Hep G(2) cell line was stably transduced with an expression vector containing the alpha1BR cDNA, the cell line responded to phenylephrine treatment with enhanced proliferation and with decreased tTG cross-linking activity. Ethanol treatment of the alpha1BAR-transfected cells suppressed the phospholipase C-mediated signaling pathways, as detected in the phenylephrine-induced Ca(2+) response. These results suggest that phenylephrine stimulation of hepatocyte proliferation appears to be occurring through the alpha1BAR, which is known to be coupled with the tTG G protein moiety, Galpha(h), and that tTG appears to play a significant role in either enhancing or inhibiting hepatocyte proliferation, depending on its cellular location and on whether it functions as a cross-linking enzyme or a G protein.

Animals↗

PubMed2000

Involvement of Sp1 in the transcriptional regulation of the rat insulin-like growth factor-1 gene.

UNLABELLED: Most insulin-like growth factor-I (IGF-I) transcripts are initiated in exon 1, but mechanisms of regulation are not well understood. Since potential Sp1 sites are found in footprinted regions within approximately 360 bp upstream and downstream from the major initiation sites in exon 1, we explored the involvement of Sp1 and Sp3 in regulation of IGF-1 expression. Gel shift assays showed strong Sp1 binding to the downstream site, but binding to the upstream site was weak; Sp1 bound to a CCTGCCCA sequence in downstream footprint region V, and Sp3 binding was centered on the same sequence. IGF-I basal promoter constructs containing a mutation in the downstream Sp1 site exhibited a 32% decrease in expression in CHO cells and a 75% decrease in HepG2 cells, indicating the importance of Sp1 for expression in vivo. Sp1 and Sp3 expression vectors provided three- to five-fold stimulation of wild-type IGF-I constructs, but had little effect on a construct containing a mutation in the downstream Sp1 site, and Sp1 had comparable effects in Drosophila SL2 cells. IGF-I heterologous promoter constructs exhibited similar responses: in both SL2 cells and CHO cells, stimulation by Sp1 was enhanced with constructs containing downstream region V. Since Sp1 also stimulated expression of concatamers of putative cis-acting sites fused to the SV40 promoter enhancer in pGL3, the results in combination indicate that the presence of IGF-I region V is sufficient to permit stimulation by Sp1. CONCLUSION: Sp1 and related factors may play an important role in the regulation of IGF-I gene transcription, through interactions with region V downstream from the major initiation sites in exon 1.

Animals↗

PubMed2000

Fatal occupational injuries in a new development area in the People's Republic of China.

Fatal occupational injuries in a new development region in Shanghai in east China are described. All occupational deaths in the East Pujiang New Area during the period 1991 through 1997 were abstracted from multiple, overlapping source documents. There were 426 deaths and a crude mortality rate of 9.1 per 100,000 workers. The death rate was highest in 1995 (14.6%), when expansion in the area was most rapid. The construction sector accounted for 55% of the deaths, followed by manufacturing (23%) and transport, storage, and telecommunications (11%). Falls, collisions, struck by/against incidents, and electrocutions accounted for 80% of all deaths. Falls led all other causes of deaths (33%) and were particularly prevalent in the construction industry (46% of all deaths in construction). The development of ongoing, comprehensive injury surveillance systems in the People's Republic of China will be essential to target and evaluate injury prevention activities in the future.

Accidents, Occupational↗

PubMed2000

[Epidemiology of dental caries and periodontal diseases in middle school students in Suzhou City].

OBJECTIVE: To assess the prevalence of dental caries and periodontal diseases in middle school students at the ages of 11 to 13 and 15 to 17. METHODS: Dental caries and periodontal diseases were assessed strictly by "national survey table of dental caries and periodontal diseases for school students". RESULTS: The study group consisted of 20 581 students. The percentage of dental caries, DMFT and DMFS in students 11 to 13 years of age were 23.6%,0.40 and 0.54, respectively. The corresponding results were 29.76%, 0.64 and 0.87 for students 15 to 17 years of age, respectively. The percentage of gingivitis and dental calculus in students 11 to 13 years were 75.33% and 35.86%, respectively. The corresponding values in students 15 to 17 years of age were 73.1% and 44.91%, respectively. Female students have significantly few gingivitis and dental calculus than male students in both groups. CONCLUSION: Compared with the students at the same ages in other cities, students in Suzhou city have low percentage of dental caries and periodontal diseases.

English Abstract↗

PubMed1999

A study on oxidative stress in lead-exposed workers.

To explore the possible oxidative stress induced by lead, heparinized whole blood and urine of 66 secondary smelter lead workers (46 for Comet assay) and 28 controls were collected. The concentrations of blood lead (BPb) and urinary lead (UPb) and alpha-aminolevulinic acid (alpha-ALA), indices of lead exposure level of the body, were determined. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity of plasma were also measured. Single-cell gel (SCG, Comet assay) was used to measure the DNA damage of peripheral blood cells. There was a positive correlation between the presence of Pb in blood and significant increases in MDA levels and SOD activity. Alcohol consumption and smoking with increased exposure to Pb was associated with enhanced DNA damage. A positive correlation was found between MDA and DNA damage.

Adult↗

PubMed1999

Effects of class III antiarrhythmic agents in an in vitro rabbit model of spontaneous torsades de pointe.

Acquired long QT syndrome develops as a result of pharmacological interventions that prolong action potential duration. Excessive action potential prolongation may lead to torsade de pointes, a potentially fatal arrhythmia. To study this arrhythmia, in vivo models have been developed, but are difficult to interpret due to the complex nature of the intact metabolic, nervous and humoral systems. To more clearly examine the propensity of various Class III agents to elicit torsades de pointe, an in vitro model of spontaneous torsades de pointe was used in isolated perfused rabbit hearts. Male New Zealand white rabbits were anesthetized with sodium pentobarbital, and hearts isolated and perfused in a Langendorff apparatus. Electrocardiogram and epicardial monophasic action potentials were continuously recorded, and methoxamine (30 nM) and acetylcholine (0.3 microM) were given throughout the experiment. After 10 min of methoxamine and acetylcholine perfusion, Class III agents, dofetilide (0.1 to 0.7 microM), E-4031 (0.1 to 0.5 microM), D-sotalol (10 to 30 microM), or clofilium (0.1 to 0.3 microM), were given. All agents, except D-sotalol, induced torsades de pointe in 100% of hearts tested. D-Sotalol (30 microM) elicited a low incidence of torsades de pointe (25%). This could be explained by the limited prolongation of action potential duration with D-sotalol as compared to other Class III agents under these conditions. Dofetilide, a selective Class III agent, alone did not induce torsades de pointe. Nadolol (3 microM), a beta-adrenoceptor antagonist, increased the propensity of dofetilide to elicit torsades de pointe. In conclusion, increases in action potential duration (i.e., using Class III agents) in combination with a low heart rate (muscarinic receptor stimulation) and increases in intracellular Ca2+ (alpha-adrenoceptor stimulation) are needed to develop torsades de pointe in this model. Modulating these systems may provide us with new insights into preventing the initiation or maintenance of this arrhythmia.

Acetylcholine↗

PubMed1999

Identification of core sequences involved in metabolism-dependent nuclear protein binding to the rat insulin-like growth factor I gene.

In the liver, most insulin-like growth factor I (IGF-I) transcripts originate in exon 1, where important cis-regulatory regions are located downstream from the major transcription initiation sites. Within these regions, we have attempted to identify sequences which are involved in the decrease in IGF-I gene transcription associated with diabetes mellitus. The function of different genomic templates was assessed by in vitro transcription, which revealed a consistent 50-80% decrease in the activity of nuclear extracts from streptozotocin-diabetic as compared with normal rats. The disparity in transcriptional activity between normal and diabetic nuclear extracts was reduced with templates containing 11-bp mutations within DNase I protected regions III or V (+42 and +129 bp, respectively, from the major transcription initiation site), but a mutation between regions IV and V had little effect. Within region III, gel mobility shift analysis and methylation interference studies indicated that DNA-protein interactions involve a GCGC core sequence. In region V, gel mobility shift studies and uracil interference analysis revealed interactions involving a TTAT core. While gel mobility shift analysis and transient transfection studies indicate that the GCGC core sequence in region III recognizes C/EBP, the AT-rich sequence in region V is likely to recognize a protein with homeodomain characteristics. Identification of the nuclear factor(s) interacting with regions III and V, downstream from exon 1 initiation sites, will be important for understanding the mechanism of reduced IGF-I gene transcription due to diabetes mellitus.

Animals↗

PubMed1998

Increased liver uptake of liposomes and improved targeting efficacy by labeling with asialofetuin in rodents.

To improve liposome-directed therapy of liver disease and gene delivery, it would be beneficial to selectively target hepatocytes. For this purpose, conventional liposomes (CL) were labeled with asialofetuin (AF), an asialoglycoprotein. The biodistribution of AF-labeled liposomes (AF-L) in mice and their incorporation into rat hepatocytes, and their potential use in acute liver injury, were investigated. AF-L displayed a quicker plasma clearance than CL, and 25.4%, 2.7%, and 1.2% of the injected dose remained in the plasma versus 47.0%, 26.1%, and 9.5% of CL, respectively at 2, 4, and 20 hours after the injection. Total liver uptake of AF-L (73%+/-3.9%) was markedly higher (P < .005) than CL (16.5%+/-1.8%) 4 hours after the injection. Liposomal radioactivity (cpm/mg) was greatly enhanced in the liver (11-fold) during the first 4 hours after the administration of 14C-AF-L, and was much higher than in 14C-CL-injected mice (1.5-fold). In vitro incubation of isolated rat hepatocytes with 14C-AF-L or intravenous injection of 14C-AF-L in rats resulted in higher hepatocyte-bound radioactivity compared with 14C-CL (P < .01-.005). AF-L-associated 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) fluorescent signals were not only located in Kupffer cells, but also in hepatocytes, in which bile canaliculus networks were imaged. Intravenous administration of vitamin E (VE)-associated CL (VE-CL, 1 mg/mouse) significantly lowered alanine transaminase (ALT) levels in CCl4-treated mice (196+/-79 vs. 2,107+/-235 U/mL; P < .01). The ALT level in CCl4 + VE-AF-L group was decreased to 38+/-16 units/mL, which was significantly lower than the CC14 + VE-CL group (P < .05). In conclusion, labeling liposomes with AF led to a shortened liposome plasma half-life and greatly enhanced uptake of AF-L liposome by the liver. The enhanced uptake resulted from an increased incorporation of hepatocytes with AF-L liposomes. VE-associated AF liposomes further improved the protective effect of VE liposomes on CC14-induced acute liver injury in mice. Preferential hepatocyte incorporation of AF-L liposomes suggests a useful hepatocyte-targeting approach for drug delivery and gene transfection.

Alanine Transaminase↗

PubMed1998

Proarrhythmic effects of pinacidil are partially mediated through enhancement of catecholamine release in isolated perfused guinea-pig hearts.

The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30 microM), an opener of ATP-sensitive potassium channels (K+ATP), was tested in an isolated guinea-pig heart model of global ischemia (10 min) and reperfusion (10 min). None (0%) of the control hearts (n=10) elicited arrhythmias during ischemia or reperfusion. In the pinacidil-treated group, one heart (5%) experienced episodes of ventricular tachycardia (VT)/fibrillation (VF) during normoxia. During ischemia, 63% (12 out of 19) of pinacidil-treated hearts exhibited episodes of VT or VF. Hearts not in VT or VF (n=7) at the time of reperfusion, exhibited 71% VT and 43% VT/VF upon reperfusion. Proarrhythmic effects of pinacidil during ischemia or reperfusion were completely reversed by glyburide (n=9; 10 microM), a K+ATP antagonist, or nadolol (n=9; 3 microM), a beta-adrenergic antagonist. Isoproterenol (n=10; 50 nM), a beta-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10 microM), an alpha-adrenergic agonist, demonstrated little proarrhythmia (20% VT/VF at reperfusion only). Proarrhythmic effects of isoproterenol were reversed by nadolol, but not glyburide. Pinacidil caused a slight potentiation of tachycardia induced by a bolus injection of tyramine (30 micro g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 micro g) had no effect on heart rate. Nisoxetine, a catecholamine uptake 1 inhibitor, had no proarrhythmic effects when given alone. Catecholamine levels were reduced in pinacidil-treated hearts relative to vehicle-treated. In conclusion, it is suggested that the proarrhythmic effects of pinacidil following global ischemia and reperfusion in the isolated perfused guinea-pig heart appears to involve stimulation of beta-adrenoceptors. These proarrhythmic effects of pinacidil do not appear to be mediated solely through direct opening of K+ATP, but rather through an indirect enhancement of catecholamine release.

Adenosine Triphosphate↗

PubMed1995

Prior immunity-related medical conditions and pancreatic-cancer risk in Shanghai.

To investigate the role of immunity-related medical conditions in the etiology of pancreatic cancer, we analyzed data from a population-based case-control study of pancreatic cancer conducted in Shanghai during 1992 and 1993. Information on prior histories of selected auto-immune diseases and allergic conditions was obtained from 108 incident pancreatic-cancer cases and 275 age- and gender-frequency matched controls by face-to-face interviews using a structured questionnaire. A prior history of auto-immune diseases was associated with a 2-fold elevated risk of pancreatic cancer (95% CI = 1.0-4.2), with an indication of a dose-response relation for the number of reported diseases. In contrast, a prior history of allergic condition was related to reduced risk (OR = 0.6, 95% CI = 0.4-1.1). With the possible exception of drug allergy, such an inverse association was seen for virtually all allergic conditions., although none of the OR was statistically significant. This study suggests that host immune function may be involved in the etiology of pancreatic cancer. Further investigations into the mechanism of these observed associations are warranted.

Adult↗

PubMed1995

Transcriptional regulation of the rat insulin-like growth factor-I gene involves metabolism-dependent binding of nuclear proteins to a downstream region.

Insulin-like growth factor-I (IGF-I) gene transcription is mediated largely via exon 1. In an initial search for regulatory regions, rat hepatocytes were transfected with IGF-I constructs. Since omission of downstream sequences led to reduced expression, we then used in vitro transcription to evaluate potential metabolic regulation via downstream regions. With templates including 219 base pairs of downstream sequence, transcriptional activity was reduced 70-90% with hepatic nuclear extracts from diabetic versus normal rats. However, activity was comparable with templates lacking downstream sequences. The downstream region contained six DNase I footprints, and templates with deletion of either region III or V no longer provided reduced transcriptional activity with nuclear extracts from diabetic rats. Nuclear protein binding to regions III and V appeared to be metabolically regulated, as shown by reduced DNase I protection and activity in gel mobility shift assays with nuclear extracts from diabetic rats. Southwestern blotting probes corresponding to regions III and V recognized a approximately 65-kDa nuclear factor present at reduced levels in diabetic rats. These findings indicate that a downstream region in exon 1 may be important for both IGF-I expression and metabolic regulation. Altered concentration or activity of a transcription factor(s) binding to this region may contribute to reduced IGF-I gene transcription associated with diabetes mellitus.

Animals↗

PubMed1995

5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil.

5-Fluorouracil (5-FU) is an effective antitumor agent used in treating various cancers. Because of its metabolism by intestinal and other cells, 5-FU has an inconsistent bioavailability that limits its oral use. 5-Fluoro-2-pyrimidione (5-FP), a 5-FU prodrug, was synthesized and found to be converted to 5-FU by aldehyde oxidase, an enzyme present in high concentrations in the livers of mice and humans but not in the gastrointestinal tract. Using BDF1 mice, the pharmacokinetics of 5-FP were studied and compared with those of 5-FU. The bioavailability of 5-FP given orally was 100% at a dosage of 25 mg/kg and 78% at a dosage of 50 mg/kg. The half-lives of both doses of 5-FP were at least 2-fold longer than the half-lives of the same doses of 5-FU, and the clearance rates of 5-FP were 3-fold slower. 5-FP was converted rapidly to 5-FU, in vivo. The resulting 5-FU was measured at a steady-state level of 40-70 microM in plasma, at a dosage of 25 mg/kg, that was sustained for at least 4 hr. Also, when given orally, 5-FP was shown to have potent activity against Colon 38 tumor cells and P388 leukemia cells in mice. The therapeutic index of 5-FP was similar to that of 5-FU in these mouse tumor models. The potential clinical use of 5-FP as a prodrug of 5-FU should be considered.

Administration, Oral↗