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991.
Enzymes involved in the bioactivation of 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone in patas monkey lung and liver microsomes 总被引:1,自引:2,他引:1
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent
tobacco-specific carcinogen in animals. Our previous studies indicated that
there are differences between rodents and humans for the enzymes involved
in the activation of NNK. To determine if the patas monkey is a better
animal model for the activation of NNK in humans, we investigated the
metabolism of NNK in patas monkey lung and liver microsomes and
characterized the enzymes involved in the activation. In lung microsomes,
the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde),
4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK- N-oxide),
4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), and 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was observed, displaying
apparent Km values of 10.3, 5.4, 4.9, and 902 microM, respectively. NNK
metabolism in liver microsomes resulted in the formation of keto aldehyde,
keto alcohol, and NNAL, displaying apparent Km values of 8.1, 8.2, and 474
microM, respectively. The low Km values for NNK oxidation in the patas
monkey lung and liver microsomes are different from those in human lung and
liver microsomes showing Km values of 400-653 microM, although loss of low
Km forms from human tissue as a result of disease, surgery or anesthesia
cannot be ruled out. Carbon monoxide (90%) significantly inhibited NNK
metabolism in the patas monkey lung and liver microsomes by 38-66% and
82-91%, respectively. Nordihydroguaiaretic acid (a lipoxygenase inhibitor)
and aspirin (a cyclooxygenase inhibitor) decreased the rate of formation of
keto aldehyde and keto alcohol by 10-20 % in the monkey lung microsomes.
Alpha-Napthoflavone and coumarin markedly decreased the oxidation of NNK in
monkey lung and liver microsomes, suggesting the involvement of P450s 1A
and 2A6. An antibody against human P450 2A6 decreased the oxidation of NNK
by 12-16% and 22-24% in the patas monkey lung and liver microsomes,
respectively. These results are comparable to that obtained with human lung
and liver microsomes. Coumarin hydroxylation was observed in the patas
monkey lung and liver microsomes at a rate of 16 and 4000 pmol/min/mg
protein, respectively, which was 5-fold higher than human lung and liver
microsomes, respectively. Immunoblot analysis demonstrated that the P450 2A
level in the individual patas monkey liver microsomal sample was 6-fold
greater than in an individual human liver microsomal sample. Phenethyl
isothiocyanate, an inhibitor of NNK activation in rodents and humans,
decreased NNK oxidation in the monkey lung and liver microsomes displaying
inhibitor concentration resulting in 50% inhibition of the activity (IC50)
values of 0.28-0.8 microM and 4.2-6.8 microM, respectively. The results
demonstrate the similarities and differences between species in the
metabolic activation of NNK. The patas monkey microsomes appear to more
closely resemble human microsomes than mouse or rat enzymes and may better
reflect the activation of NNK in humans.
相似文献
992.
The magnetic resonance imaging (MRI) characteristics of 15 cases of tuberculous (TB) spinal infection were reviewed. The commonest site was the lumbar spine (53.3%), often with three or more contiguous vertebrae involved (47%). Destruction of the vertebral body and the presence of paraspinal soft-tissue masses were noted in 73.3%. Posterior element abnormalities, which is a significant finding, were seen in 40%, a slightly lower incidence rate than in other reported series. Epidural disease (53.3%) and disc abnormalities (73%) were more frequent than was realized. The role of intravenous contrast is discussed. Intravenous gadolinium is useful because it increases diagnostic confidence by characterizing and delineating the disease process, detects reactivation in old and healed TB, helps in treatment management and may prove valuable in monitoring therapy. Magnetic resonance imaging should be considered to be the imaging modality of choice for patients with suspected tuberculous spinal infection. 相似文献
993.
Jiao D; Smith TJ; Yang CS; Pittman B; Desai D; Amin S; Chung FL 《Carcinogenesis》1997,18(11):2143-2147
A series of L-cysteine (L-Cys), glutathione (GSH), and N-acetyl-L- cysteine
(NAC) conjugates of phenethyl (PEITC), benzyl (BITC), and 6- phenylhexyl
isothiocyanate (PHITC) were studied for their inhibitory activity toward
metabolic activation of the tobacco-specific nitrosamine
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mouse lung
microsomes. Selected compounds, PEITC, PEITC-GSH, PEITC-NAC and PHITC-NAC,
were also assayed for the potential chemopreventive activity toward
NNK-induced lung tumorigenesis in A/J mice. Results showed that PEITC and
its conjugates inhibited NNK metabolism with decreasing potency: PEITC <
PEITC-GSH > PEITC-Cys > PEITC-NAC. PHITC and its GSH and NAC
conjugates exhibited nearly 10 times higher inhibitory activity toward NNK
metabolism than the PEITC counterparts. In the tumor bioassay, as expected,
the conjugates exhibited inhibitory activity against lung tumorigenesis
induced by NNK. PEITC-GSH was not inhibitory at 4 micromol/mouse, but it
inhibited approximately 32% of lung tumor multiplicity at 8 micromol/mouse.
PEITC-NAC at 5 and 20 micromol/mouse both inhibited approximately 30% tumor
multiplicity. Among all the conjugates examined, PHITC-NAC was the most
potent. At a 5-micromol dose, it completely inhibited tumor multiplicity
and incidence to the background level observed in the control group. These
results revealed that the structure-activity relationships of the
conjugates are similar to those found with their parent isothiocyanates
(ITCs), i.e., the potency increased with the increasing alkyl chain length
from two to six carbons in arylalkyl ITCs, suggesting that a common active
species is involved. The inhibitory activity of ITC conjugates and the
expected low toxicity make thiol conjugates of ITC a promising new series
of chemopreventive agents.
相似文献
994.
A human gonadotrophin releasing hormone (GnRH) upstream promoter/luciferase
reporter gene construct (H2 construct) was generated by inserting a 1.7 kb
XbaI/AflII fragment containing the human GnRH upstream promoter region only
into a promoter-less luciferase reporter vector. When JEG-3 cells were
transiently transfected with this construct and treated with cortisol or
its synthetic analogue dexamethasone, a stimulatory effect on the upstream
promoter activity was observed. This stimulation was dependent on the
cotransfection of a glucocorticoid receptor (GR) cDNA expression vector due
to the low level of GR in JEG-3 cells and could be completely abolished by
RU486, a glucocorticoid antagonist. Moreover, the cortisol actions could be
modulated to a different extent by oestradiol. Thus, since the human
placenta contains GRs and the increase in cortisol metabolism near term is
regulated by oestrogen, the current findings suggest that cortisol may be
physiologically involved in the regulation of GnRH gene expression in the
human placenta.
相似文献
995.
Mutations that produce glucose-6-phosphate dehydrogenase (G6PD) deficiency have been identified in samples from patients with hemolytic disease in the United States, and in G6PD-deficient samples from Greece, the Canary Islands, the Czech and Slovak Republics, South China, and in samples from the Coriell Cell Repository. Eight new mutations are described. Particularly unusual were a nonsense mutation ("G6PD Georgia"1284A), a deletion of six bases ("G6PD Stony Brook" 724- 729 del) coding for two amino acids, and a deletion of the invariant dinucleotide ApG at the 3' acceptor splice site in the highly conserved sequence between intron 10 and exon 11 ("G6PD Varnsdorf"). In addition, five new missense point mutations were identified: "G6PD Cleveland"820A creates a deduced AA 274 Glu-->Lys; "G6PD West Virginia"910T AA 303 Val- ->Phe; "G6PD Fushan"1004A, AA 335 Ala-->Asp; "G6PD Olomouc"1141C AA 381 Leu-->Phe; and "G6PD Praha"1166G AA 389 Glu-->Gly. All of the new mutations except for "G6PD Fushan"1004A were found in patients with hereditary nonspherocytic hemolytic anemia. A coincidental finding in the case of G6PD "West Virginia" was a C-->T transition at nucleotide 1,191. This silent mutation, Asn-->Asn, appears to be rare. Haplotype analysis of mutations in samples from the Canary Islands and South China agreed with previous findings. 相似文献
996.
Thomas E. Elliott MD ; Barbara A. Elliott PhD ; Ronald R. Regal PhD ; Colleen M. Renier BS ; Irina V. Haller PhD MS ; Byron J. Crouse MD ; Martha T. Witrak PhD RN ; Patricia B. Jensen MEd RN CS 《The Journal of rural health》2004,20(1):26-35
CONTEXT: Significant barriers exist in the delivery of state-of-the-art cancer care to rural populations. Rural providers' knowledge and practices, their rural health care delivery systems, and linkages to cancer specialists are not optimal; therefore, rural cancer patient outcomes are less than achievable. PURPOSE: To test the effects of a strategy targeting rural providers and their practice environment on patient travel for care, satisfaction, economic barriers, and health-related quality of life. METHODS: A group-randomized trial was conducted with 18 rural communities in the north-central United States. Twelve of these communities were included and defined as the unit of analysis for the patient outcomes portion of the study. The intervention targeted rural providers and their practice environment. The subjects were patients with breast, colorectal, lung, and prostate cancers from the rural communities. The main outcomes were patients' travel to obtain health care, satisfaction with care, perceptions of economic barriers to care, and health-related quality of life. In total, 881 patients were included. RESULTS: Group randomization was balanced. Travel for health care was significantly reduced in the community group exposed to the intervention during months 13 to 24 following cancer diagnosis. The mean miles traveled per patient were 1,326 (SE = 306) for the experimental group and 2,186 (SE = 347) for the control group (P = 0.03). No significant differences in satisfaction with care, economic barriers to care, or health-related quality of life were found. CONCLUSIONS: The intervention significantly reduced cancer patient travel for health care, which suggests that access to care improved in the experimental group. The results of this study do not allow conclusion that there was no effect on other patient outcomes. The results supported the study's conceptual framework and many of its hypotheses. 相似文献
997.
998.
Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity 总被引:3,自引:0,他引:3
Model cell lines developed from MCF7 breast carcinoma cells were used to
examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug
resistance protein (MRP) in the protection of cells from 4- nitroquinoline
1-oxide (4NQO) toxicities. Increased expression of GSTP1- 1 alone in MCF7
cells results in limited protection from the formation of 4NQO-derived
covalent adducts of nucleic acids but affords no protection from
4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred
modest protection while co-expression of GSTP1-1 with MRP produced
high-level protection from both 4NQO-derived adduct formation and 4NQO
cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic
acid adduct formation and cytotoxicity) is associated with a
GSTP1-1-dependent increase in 4NQO-glutathione (QO- SG) conjugate formation
and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP
is an important export transporter for the glutathione conjugate of the
carcinogen, 4NQO. Moreover, this MRP- dependent efflux activity is
necessary to achieve the full protection from 4NQO toxicity-protection that
is potentiated by GSTP1-1-mediated QO-SG formation.
相似文献
999.
CS Beardsmore 《Acta paediatrica (Oslo, Norway : 1992)》1993,82(S390):95-97
1000.
Previous studies that have examined the psychosocial adjustment of children with short stature have often been flawed, for two main reasons: first, a lack of sample homogeneity and, secondly, the measures of adjustment used have been limited in terms of their sensitivity. This paper examines psychological functioning in the following four broad areas: cognition, social behaviour, emotional adjustment and self-concept. A sample of children referred to growth clinics (mean height below -2 SDS) and a comparison group, recruited from the referred childrens'classes at school, were assessed. Children were prepubertal (age range, 6-11 years) and had no organic cause for their short stature. Parent, teacher and peer reports were used in the assessment, which included sociometric measures in the classroom. The children with short stature described themselves as equally well supported as the comparison children in terms of social support by parents, teachers, peers and friends. Peers reported the short children to be well accepted within their class. Compared with control children, there was a trend for short children to be described by their peers as socially better adjusted than average. Teacher and parental accounts revealed significant group differences in terms of reported behaviour, with poorer attention and more thought problems among the children with short stature. Further analysis suggested, however, that their slightly lower IQ than children of normal height (95.8 ± 18.7 (mean ± SD) compared with 105 ± 15.4) accounted for a greater proportion of the variance in these findings than short stature per se. There is little evidence to indicate that short prepubertal children are psychosocially maladjusted. Their academic performance was poorer than expected on the basis of their cognitive abilities. Reports of immature and impulsive behaviour may not be applicable to a sample of children not referred to a growth clinic. 相似文献