摘要:

AbstractIn this paper we will discuss the genetic consequences of drug interaction in tuberculosis patients. Blood from tuberculosis patients was cultured before, during, and after withdrawal of therapy involving five different drug combinations of isoniazid (INH), thiacetazone (TAZ), para‐aminosalicylic acid (PAS), and streptomycin (SM). The approaches used to detect DNA damage were chromosome aberrations and sister chromatid exchanges (SCEs). A total of 179 subjects were analyzed. In combination these drugs showed synergistic, additive, and antagonistic effects, though they were found to be nonclastogenic individually. Four of the drug combinations, INH+TAZ, INH+PAS, INH+TAZ+SM, and INH + PAS + SM, induced a significant increase in the frequency of aberrations, whereas INH+SM did not induce aberrations. In fact, SM appeared to reduce the frequency of aberrations. SCEs were increased in only two patients: one treated with INH + TAZ and the other with INH + PAS. The frequency of aberrations after withdrawal of therapy was decreased; it was slightly higher than the controls, though it was insignificant. The return to normalcy could be due to elimination of damaged cells or the repair of DNA in lymphocytes. Though the drug‐induced aberrations do not persist after withdrawal of therapy, the chromosome damaging combinations of drugs should be used with caution, because the possibility of meiotic chromosome damage in germ cells (during therapy), which might be passed on to the next generation, cannot be ruled

ISSN:0270-3211    

DOI:10.1002/tcm.1770040302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractThe embryotoxic, mutagenic, and cytotoxic properties of 2‐acetylaminofluorene (AAF) and two of its reactive metabolites, N‐acetoxy‐2‐acetylaminofluorene (AAAF) and 2‐nitrosofluorene (NF) were assessed in vitro. A combined embryo culture/biotransformation system was used to determine the ability of these compounds to produce embryonic malformations, growth retardation, and/or embryolethality.Salmonella typhimuriumauxotrophs (his−) were utilized to measure the mutagenic and cytotoxic potentials of these compounds.The parent compound, AAF, did not produce embryonic malformations or mutagenicity in the absence of an added cytochrome P‐450‐dependent monooxygenase system. Both metabolites produced each of the measured toxic effects without supplementation of a bioactivation system. However, the three chemicals each elicited a different spectrum of malformations. Bioactivated AAF produced neural tube abnormalities, whereas embryos treated with AAAF primarily exhibited prosencephalic malformations, and NF produced abnormalities of axial rotation or flexure. NF was approximately ten times more potent than AAAF as a direct‐acting mutagen but only slightly more active in producing embryonic malformations in vitro. The results indicated that differential effects on the various measured parameters could be produced by these chemicals. The results indicated further that neither NF nor AAAF appeared to be individually responsible for the neural tube abnormalities generated by b

ISSN:0270-3211    

DOI:10.1002/tcm.1770040303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractCell‐cell communication through chemical messengers is a fundamental event required for the differentiation of embryonal cells. Interference with this process by xenobiotics may disrupt embryogenesis. Chinese hamster cells (V79) which display a specific form of cell‐cell communication called metabolic cooperation were cultured in the presence of structurally diverse chemical teratogens. Among them were 12‐0‐tetradecanoyl‐phorbol‐13‐acetate (TPA), diphenylhydantoin (DPH), warfarin, and a series of monoalkyl ethers of ethylene glycol with alcohol chain lengths from methyl to butyl. Sodium saccharin and ascorbic acid were examined to represent two chemicals which have been thoroughly tested for teratogenic effects in laboratory animals and cause no birth defects. Recovery of 100 6‐thioguanine‐resistant V79 (6‐TGr) cells in coculture with 400,000 6‐thioguanine‐sensitive V79 (6‐TGs) cells in the presence of 6‐thioguanine (6‐TG) and the chemical agent was measured. In amounts that neither interfered with colony forming ability nor caused cytostasis when 100 6‐TGr cells were plated alone, all of the substances except for saccharin and vitamin C increased the number of surviving 6‐TGr cells in a concentration‐related manner. The recovery was increased by the presence of TPA (to 100% by 4 ng/ml), DPH (from 26% at 91 μM to 43% at 274 μM), warfarin (from 15.5% at 162 μM to 44.5% at 487 μM) and to variable extents by all five glycol ethers. The most efficacious in the latter group of compounds was the isopropyl ether which raised 6‐TGr recovery from 8% at 0.017 M to 66% at 0.087 M. Based on the evidence accumulated by previous studies involving TPA, we postulate that the teratogens employed inhibited metabolic cooperation. These observations suggest that V79 cells may be suitable to study inhibition of cell‐cell co

ISSN:0270-3211    

DOI:10.1002/tcm.1770040304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractAnimal studies of endotoxemia during pregnancy have suggested that the placenta is the primary site of action. This study was designed to evaluate the effects of endotoxin at previously established resorptive and teratogenic dose levels during the development of the placenta in the hamster. At the higher dose levels, total necrosis of the placenta was observed within 24 hr after treatment. Formation of fibrin thrombi was only apparent well after the initiation of necrotic events. At the teratogenic dose, a marked decrease in the formation of the placental labyrinth was evident, but invading fetal capillaries and fetal blood cells appeared normal. However, scattered necrotic foci of trophoblastic cells were observed.

ISSN:0270-3211    

DOI:10.1002/tcm.1770040305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

摘要:

AbstractRetinoic acid, suspended in cottonseed oil, was administered via gavage to pregnant mice (ICR strain) on day 11 (E 11) of gestation at doses of either 20, 40, or 80 mg/kg. Fetuses were examined for external malformations on day 17 (E 17). Retinoic acid treatment induced micromelia (with the elimination of several long bones at higher doses) and digital defects (ectrodactyly and syndactyly) in a dose‐dependent manner in fetuses examined on day 17. Hindlimbs were affected more than forelimbs. In another group of experiments, limbs exposed to retinoic acid treatment in utero on E 11 were cultured on E 12 and maintained for 3 days in submerged culture. Cultured limbs were examined qualitatively for digital and long bone defects, and image analysis of the area and form of bone anlagen of cultured limbs was used to quantitatively evaluate the teratogenic potential of retinoic acid. The qualitative evaluation indicated that the retinoic acid‐induced effects obtained in vivo and with pretreated, cultured limbs were essentially the same, except that the severity of regional effects changed as a result of culture. The incidence of ectrodactyly was higher with cultured limbs than with E 17 fetal limbs, but fewer cultured limbs were missing long bones. These results suggest that culturing limbs, after they have been pretreated in utero, modifies their response to a teratogen and demonstrates that the paw skeleton is extremely sensitive to teratogen treatment under these experimental conditions. Therefore, care must be exercised when attempting to compare in vivo and in vitro teratogenic data. This study also clearly demonstrates the power and usefulness of image analysis for quantitative evaluation of both the area and form of a cultured specimen such as the developing limb bud. Quantitative, image analysis of cultured limbs showed a dose‐dependent decrease in area of both fore‐ and hindlimbs. The effect was most severe in hindlimbs. In the forelimb, the paw was affected more than the long bones; as the dose increased, this disparity of effect also increased. With the hindlimb, a greater effect on the paw occurred only at 80 mg/kg. Computing the soft tissue/bone ratio illustrated that retinoic acid had a greater effect on chondrogenic tissue than on soft

ISSN:0270-3211    

DOI:10.1002/tcm.1770040306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770040301

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1984

数据来源: WILEY