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Biomedical subjects

L K Lambrecht

Publications and source records attributed to L K Lambrecht.

At least 19 recordsLinked to original sources
PubMed1993

Synergistic induction of cytochrome P450 by ethanol and isopentanol in cultures of chick embryo and rat hepatocytes.

The purpose of this study was to investigate whether isopentanol, the most abundant higher chain alcohol in alcoholic beverages, contributes to induction of different forms of hepatic P450s associated with consumption of these beverages. We have previously reported that ethanol and isopentanol each induce P450 2H1/2 in cultured chick hepatocytes and that ethanol induced P450 2B1/2, as well as P450 2E, in cultured rat hepatocytes. Here we investigated the induction of P450 by isopentanol alone and in combination with ethanol in cultured chick and rat hepatocytes. The forms of induced P450 were identified both enzymatically and immunochemically. In cultured chick hepatocytes, both isopentanol and ethanol induced P450 2E, but combined treatment with these alcohols had no greater effect than treatment with ethanol alone. In cultured rat hepatocytes, isopentanol alone did not induce P450 2E or 2B1/2 and had no effect on the ethanol-mediated induction of P450 2E. However, isopentanol combined with ethanol caused a synergistic induction of P450 2B1/2 in cultured rat hepatocytes and an additive to synergistic induction of P450 2H1/2 in cultured chick hepatocytes. The levels of enzyme activities induced by the combined alcohol treatment approached those induced by potent barbiturates. The results suggest that the pentanols in alcoholic beverages may be responsible for a barbiturate-like induction of P450 in hepatocytes.

Animals↗
PubMed1992

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline induces and inhibits cytochrome P450 from the IA subfamily in chick and rat hepatocytes.

Several heterocyclic amines, found in cooked food, are powerful mutagens in the Ames Salmonella mutagenicity test system. One of these, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is one of the most mutagenic chemicals tested in this assay. In primary cultures of chick and rat hepatocytes, MeIQ, by itself, induced cytochrome P450 from the IA subfamily but was a weak inducer compared to 3-methylcholanthrene. However, in both chick and rat hepatocytes in culture, MeIQ decreased the amount of 3-methylcholanthrene-induced ethoxyresorufin deethylase activity, which is catalyzed by cytochrome P450 IA. The protein moiety of cytochrome P450 IA was decreased at MeIQ concentrations of 2.5 micrograms/ml or greater in chick hepatocytes and 25 micrograms/ml in rat hepatocytes. In hepatic microsomes from methylcholanthrene-treated chicks and rats, MeIQ was a competitive inhibitor of both ethoxyresorufin deethylase activity, a reaction catalyzed mainly by rodent cytochrome P450 IA1, and uroporphyrinogen oxidation, a reaction catalyzed by rodent P450 IA2. In cultured chick hepatocytes, MeIQ also decreased cytochrome P450-mediated oxidation of uroporphyrinogen by intact cells. The ability of MeIQ to inhibit as well as to induce cytochrome P450s of the IA subfamily may be important in assessing the mutagenic and carcinogenic effects of MeIQ in mammals.

Animals↗
PubMed1991

Ethanol increases cytochromes P450IIE, IIB1/2, and IIIA in cultured rat hepatocytes.

In intact rats, ethanol treatment has been associated with increases in hepatic levels of both P450IIB1/2 and P450IIE. When rat hepatocytes were cultured on an extracellular tumor matrix (Matrigel), exposure to ethanol from 48 to 96 h in culture resulted in increases in cytochromes P450IIE, IIB1/2, and IIIA. Cytochrome P450IIE was detected immunologically and enzymatically, using two activities associated with cytochrome P450IIE, p-nitrophenol hydroxylation, and acetaminophen activation to a metabolite that binds to glutathione. The content of cytochrome P450IIE in freshly isolated cells decreased when the cells were placed in culture. Exposure of the cultured hepatocytes to ethanol from 48 to 96 h after inoculation resulted in an increase in cytochrome P450IIE compared to untreated cultured cells. In addition, in culture, the amount of enzymatically active protein after ethanol treatment was equal to that in hepatocytes freshly isolated from intact animals. Ethanol treatment resulted in increases in cytochrome P450IIB1/2 compared to untreated cells, as shown immunologically and by increased benzyloxyresorufin dealkylase activity. However, phenobarbital induced cytochrome P450IIB1/2 to higher levels, compared to ethanol. Ethanol and phenobarbital treatments both increased P450IIIA, as determined immunologically and by the amount of propoxycoumarin depropylase activity that is inhibited by triacetyloleandomycin. However, the amount of P450IIIA increased after ethanol treatment was less than that increased after treatment with dexamethasone in these cells. The ethanol-mediated increases in all four forms of cytochrome P450 in culture suggest that these increases in the intact animal result from direct effects of ethanol on the liver.

Acetaminophen↗
PubMed1986

The influence of preadsorbed canine von Willebrand factor, fibronectin and fibrinogen on ex vivo artificial surface-induced thrombosis.

We have examined the effects of preadsorption of several canine plasma proteins on surface-induced thrombogenesis in a canine ex vivo model. Our technique allowed determination of initial deposition and subsequent embolization of 51Cr-labeled platelets and 125I-fibrinogen onto and from polymeric arterio-venous shunts in non-anticoagulated canines. Segments of the tubing were removed at various time points between 2 and 120 minutes of blood contact for examination of the morphology of the thrombus by scanning electron microscopy. Thrombus deposition was measured on uncoated plasticized poly(vinyl chloride) (PVC) and PVC precoated with canine von Willebrand factor (vWF), fibronectin, partially purified fibrinogen (fibrinogen which contained vWF and fibronectin as impurities), or purified fibrinogen (fibrinogen which had been further purified to remove fibronectin and vWF). Preadsorption of all proteins studied enhanced the thrombogenic response relative to that of the uncoated surface. Precoating with vWF or partially purified fibrinogen resulted in the deposition of the greatest number of thrombi, and embolization was slower than on shunts precoated with canine fibronectin or purified fibrinogen. The deposition-embolization profiles for the fibronectin and purified fibrinogen-coated surfaces were similar. The amount and time sequence of initial adhesion and spreading of platelets was related to the extent and time sequence of peak thrombus formation. The partially purified fibrinogen-coated and vWF-coated surfaces had more adhered and spread platelets at the earliest time points and a greater number of larger thrombi at the peak deposition times. The slowest rate of platelet adhesion and spreading was seen on the purified fibrinogen-coated surface. White blood cells were present very early on surfaces precoated with vWF and partially purified fibrinogen, and were present prior to embolization on all surfaces. Major conclusions from this work indicate that, although fibrinogen and fibronectin promote thrombogenesis when adsorbed to a surface, vWF is even more active in promoting platelet deposition and in anchoring thrombi to the surface of biomaterials. Thus, differences in vWF adsorption to biomaterials may be a determinant of surface-induced thrombogenesis.

Adsorption↗
PubMed1984

In vitro vs. ex vivo platelet deposition on polymer surfaces.

The initial adherence and activation of platelets on a surface may be a major determinant of the thrombogenicity of that surface. The response of platelets to four polymers: polyethylene (PE), polyvinyl chloride (PVC), silicone rubber (SIL), and oxidized polyethylene (OX-PE) was studied in vitro with scanning electron microscopy. Platelets from mongrel canines and rhesus monkeys were obtained just prior to cannulation of the donor animal with an ex vivo arteriovenous series shunt evaluating the same four polymers. Thus, the in vivo response of circulating platelets could be compared to the in vitro response of purified platelets from the same animal. In the canine the in vitro response of individual platelets deposited on the four polymers studied was nearly the same as the ex vivo response although the extent of shape-change was usually somewhat greater ex vivo. Large numbers of fully spread platelets were seen on OX-PE and fewer numbers on PE both in vitro and ex vivo. Mixtures of platelets in all degrees of shape-change/activation wer characteristic on PVC, while platelets on SIL showed little shape-change over all time intervals. Rhesus platelet response was similar to the canines' except that fewer attached or shape-changed, and differences in responses to the four polymers were less pronounced. The similarity of the in vitro to the ex vivo response in each of the species suggests that this simple in vitro model can be informative in studying platelet shape-change/activation as a precursor to surface induced thrombosis with less complexity and expense than in vivo methods.

Adenosine Diphosphate↗
PubMed1983

Physicochemical characterization and in vivo blood tolerability of cast and extruded Biomer.

Solution grade and extruded grade Biomer (SB and EB, respectively) are polyurethanes that have been suggested for use in biomedical applications. The bulk materials were examined by elemental analysis, differential scanning calorimetry, thermomechanical testing, and stress-strain testing. The extruded grade material has a lower soft segment molecular weight (650 g/mol) than the solution grade material (2000 g/mol). As a result of its higher molecular weight, the soft segment phase of SB is semicrystalline in the solid state. The hard segments of the extruded grade material are chain extended with water yielding a lower urea concentration than in the solution grade material in which the hard segments are chain extended with diamines. Chemical structures for the two materials consistent with elemental analysis, urea/urethane ratios and thermal and mechanical data, are proposed. X-ray photoelectron spectroscopy (ESCA) was used to analyze the surfaces of extruded grade Biomer, solution grade Biomer cast on the inner surface of polyethylene tubing, and extruded grade Biomer dissolved in DMA and similarly cast on polyethylene (CB). Soft segment concentrations were highest on the EB surface and lowest on the SB surface. Soft segment concentrations on the EB surface were higher than on the CB surface, indicating that the method of fabrication affected the composition of the surface layer. The three materials were tested for blood tolerance in a canine femoral arteriovenous shunt configuration. Blood compatibility was correlated with increasing concentration of polyether soft segments on the surface.

Animals↗
PubMed1983

Morphological changes occurring during thrombogenesis and embolization on biomaterials in a canine ex-vivo series shunt.

An acute canine ex-vivo femoral A-V shunt technique was used to study thrombus formation and embolization on a number of porous and non-porous polymer surfaces over a one-hour blood contact period. The technique allows for simultaneous exposure of all the surfaces under similar physiological and hematological conditions. This makes comparisons between surfaces more reliable. SEM was used to study changes in the morphology of platelets and thrombi present on the polymer surfaces. Quantitative information was obtained using radiolabeled platelets. In general, platelet deposition, activation, and aggregation was followed by thrombus formation which peaked at about 15-30 minutes of blood contact. Thrombi were composed mainly of platelets with few leukocytes present. Embolization was observed on Silastic (SIL), polyvinylchoride (PVC), polyethylene (PE), and oxidized polyethylene (OX-PE) surfaces between 20 and 60 minutes of blood contact. The mechanism for embolization involved clot retraction under the influence of a shear field. Leukocytes did not appear to be necessary for the initiation of embolization but were present during the embolization phase on OX-PE, possibly due to chemotactic factors. Although extensive thrombus formation was observed on the porous PTFE materials (GORE-TEX and IMPRA), the thrombi formed were flat and did not significantly block the lumen. By 60 minutes of blood contact, only minimal embolization had occurred on the PTFE surfaces. SEM examination of the sequence of thrombus formation and embolization was found to correlate well with trends in platelet deposition measured using radiolabeling techniques.

Animals↗
PubMed1981

Cast vs extruded Biomer for biomedical applications.

The properties of solution grade and extrusion grade Biomer have been investigated and compared. In vivo blood compatibility studies using arteriovenous (AV) shunts of the cast and extruded materials show that extruded Biomer is more thromboresistant than solution cast Biomer. This has important implications for long-term implantation studies, since solution cast Biomer is used in artificial hearts. This study also indicates that extruded Biomer, dissolved in DMA and then solution cast, is more thromboresistant than cast solution grade Biomer. Surface studies using ESCA indicate a correlation between thromboresistance and surface soft segment concentration.

Animals↗
PubMed1978

Responses of nonhuman primates to a polybrominated biphenyl mixture.

In a series of experiments, rhesus monkeys have been given in their diets 0.3, 1.5, and 25 ppm of a commercial polybrominated biphenyl (PBB) (as FireMaster FF-1). The seven adult female monkeys receiving 0.3 ppm PBB have been on the treatment regime for 15 months and have consumed over 22 mg of PBB. During the initial 6 months of exposure, they lost weight and 2 of the animals develop sterile abscesses. At 6 months, 4 of the 7 animals had flattened and lengthened serum progesterone peaks. This change was correlated with an increase in length of their menstrual cycles. After 6 months of PBB exposure, the animals were bred. Two of the 7 animals showed excessive and prolonged implantation bleeding. Two abortions and 5 live births were recorded. All of the experimental infants were smaller than the controls at birth. The animals receiving a diet containing 1.5 ppm PBB for 36 weeks (total intake 70 mg) have shown a moderate weight loss and decrease in serum cholesterol. Similar changes have also been recorded in the group given the 25 ppm PBB diet for 14 weeks (approximately 500 mg total intake). In addition, these animals have also developed a hyperplastic gastritis.

Animals↗
PubMed1977

17beta-oestradiol and Enovid mammary tumorigenesis in C3H/HeJ female mice: counteraction by concurrent 2-bromo-alpha-ergocryptine.

Chronic administration of 17beta-oestradiol (via drinking water) or the oral contraceptive Enovid (norethynodrel and mestranol) (0-1 mg injected s.c. twice weekly) to nulliparous C3H/HeJ female mice, beginning at one month of age and terminating at 20 months (17beta-oestradiol) or 22 months (Enovid), significantly increased the incidence of mammary tumours over solvent-treated controls. Concurrent treatment of the steroid-treated mice with 2-bromo-alpha-ergocryptine (CB-154) (0-1 mg s.c. injected daily) significantly reduced mammary tumour incidence and mammary hyperplastic nodule development to the control level. CB-154 is an efficacious inhibitor of pituitary prolactin secretion. These results demonstrate that steroid-induced mammary gland dysplasias can be sharply reduced by chronic CB-154 treatment, and suggest that some of the mammary tumorigenic activities of oestrogenic steroids in C3H mice are mediated via an increased secretion of pituitary prolactin.

Animals↗
PubMed1977

Suppression of mammary tumorigenesis in C3H/He mice by ovariectomy or treatment with 2-bromo-alpha-ergocryptine: a comparison.

We compared the effects of chronic treatment with 2-Br-alpha-ergocryptine (CB-154) and of ovariectomy on the genesis of mammary hyperplastic nodules (HN) and mammary tumors in the C3H/He mouse. CB-154 is an established potent suppressor of pituitary prolactin. Eighty-five 21- to 25-day-old female mice were divided into three groups. Group I received daily sc injections of 0.1 mg CB-154. Group II was ovariectomized and group III served as controls. Mice were examined weekly for mammary tumors. Fifteen months from onset of treatment all surviving mice were killed. The mean number of HN per inguinal mammary gland, total number of mammary tumors, and number (percent) of mice with mammary tumors in each group were, respectively: controls--4.6 +/- 1.1, 41, 24/29 (83%); ovariectomized--1.2 +/- 0.6, 20, 14/28 (50%); and CB-154-treated--0.2 +/- 0.1, 16, 13/28 (46%). A significant (P less than 0.001) and equally comparable inhibition of mammary tumor incidence was observed in the ovariectomized and CB-154-treated mice. Thus early ovariectomy and CB-154 treatment (specific inhibition of prolactin secretion) appeared equally effective in the prophylaxis of mammary tumorigenesis in the C3H/He female mouse.

Adrenal Glands↗