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PubMed2003

In vitro bioactivity of silicon-substituted hydroxyapatites.

Silicon-containing hydroxyapatites were synthesized by the controlled crystallization method. Chemical analysis, N(2) adsorption, Hg porosimetry, X-ray diffraction, scanning electron microscopy-energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy (XPS) were used to characterize the hydroxyapatite and to monitor the development of a calcium phosphate layer onto the surface of the substrate immersed in a simulated body fluid, that is, in vitro bioactivity tests. The influence of the silicon content and the nature of the starting calcium and phosphorus sources on the in vitro bioactivity of the resulting materials were studied. A sample of silicocarnotite, whose structure is related to that of hydroxyapatite and contains isolated SiO(4) (4-) anions that isomorphically substitute some PO(4) (3-) anions, was prepared and used as reference material for XPS studies. An increase of the unit cell parameters with the Si content was observed, which indicated that SiO(4) (4-) units are present in lattice positions, replacing some PO(4) (3-) groups. By using XPS it was possible to assess the presence of monomeric SiO(4) (4-) units in the surface of apatite samples containing 0.8 wt % of silicon, regardless the nature of the starting raw materials, either Ca(NO(3))(2)/(NH(4))(2)HPO(4)/Si(OCOCH(3))(4) or Ca(OH)(2)/H(3)PO(4)/Si(OCOCH(3))(4). However, an increase of the silicon content up to 1.6 wt % leads to the polymerization of the silicate species at the surface. This technique shows silicon enrichment at the surface of the three samples. The in vitro bioactivity assays showed that the formation of an apatite-like layer onto the surface of silicon-containing substrates is strongly enhanced as compared with pure silicon-free hydroxyapatite. The samples containing monomeric silicate species showed higher in vitro bioactivity than that of silicon-rich sample containing polymeric silicate species. The use of calcium and phosphate salts as precursors lead to materials with higher bioactivity.

Calcium↗

PubMed2004

Advanced bioceramic composite for bone tissue engineering: design principles and structure-bioactivity relationship.

The synthesis of a new resorbable porous bioactive silica-calcium phosphate composite (SCPC) that can be used as a tissue-engineering scaffold for bone regeneration is described. The effects of chemical composition and thermal treatment on crystallization and the mechanism of phase transformation in SCPC were evaluated. In the silica-rich samples, beta-rhenanite (beta-NaCaPO(4)) and alpha-cristobalite (SiO(2)) were the dominant phases after treatment at 800 degrees C. On the other hand, in the calcium phosphate-rich samples, calcium pyrophosphate (Ca(2)P(2)O(7)) was formed in addition to beta-rhenanite and alpha-cristobalaite. X-ray diffraction analyses showed a shift in the 2 theta value of the main peak(s) of all phases indicating the formation of solid solutions. Phase transformation reactions were accompanied by a loss of water molecules that contributed to the formation of pores in the size range 10-300 microm. All SCPC samples adsorbed a significantly higher quantity of serum protein than bioactive glass (p < 0.0001). In addition, the silica-rich SCPC adsorbed a significantly higher amount of serum protein than the calcium phosphate-rich samples (p < 0.003). While the crystallization of amorphous silica into L-quartz significantly inhibited serum protein adsorption, the transformation of L-quartz into alpha-cristobalite solid solution (ss) significantly enhanced protein adsorption. On the other hand, in conjunction with the transformation of brushite (CaHPO(4)) into pyro- and tri-calcium phosphates, there was a significant decrease in protein adsorption. However, as pyro- and tri-calcium phosphates transformed into beta-rhenanite, by thermal treatment, protein adsorption increased markedly. Critical-size bone defects grafted with silica-rich SCPC were filled with new bone and contained minimal residues of the graft material. Bone defects grafted with bioactive glass enhanced new bone formation, however, with very limited resorption. The enhanced resorption of SCPC in vivo correlates well with the higher rate of silica dissolution from SCPC than bioactive glass. The facilitated Si dissolution was associated with rapid bone regeneration in defects grafted with SCPC. The enhanced bioactivity properties of the SCPC are due to its chemical composition, modified crystalline structure, and high porosity. The new SCPC may be used for a wide variety of applications in the field of bone reconstruction including tissue-engineering scaffolds for cell and drug delivery.

Animals↗

PubMed2005

Effect of particulate bioactive glasses on human macrophages and monocytes in vitro.

Bioactive glasses, originally developed to promote tissue adhesion, are finding an increasing array of biomedical applications. The aim of the current study was to assess the ability of silicate- and zinc phosphate-based bioactive glasses to modulate the secretion of cytokines from activated human macrophages and monocytes. Human macrophages and monocytes were isolated and cultured on surfaces coated with a range of quantities of the bioactive glasses. Nontoxic concentrations of the glasses were selected and assessed further for their ability to modulate the secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10 and -6, in the presence or absence of the stimulant lipopolysaccharide. 45S5 glass produced a significant reduction to the amount of TNF-alpha (p<0.05) and IL-6 (p<0.01) secreted by stimulated cells compared with cells stimulated in the absence of bioactive glass. A significant reduction in IL-6 secretion was also observed with the other silicate- and zinc phosphate-based glasses tested. IL-10 secretion was increased (but not significantly) in presence of all glasses tested. TNF-alpha and IL-6 secretion from stimulated cells was lower in presence of the silicate glasses compared with the zinc phosphate glasses, indicating that this system of bioactive glass might be of clinical use in conditions associated with inflammation.

Cells, Cultured↗

PubMed2005

Fabrication and characteristics of bioactive sodium titanate/titania graded film on NiTi shape memory alloy.

A bioactive sodium titanate/titania graded film was formed in situ on NiTi shape memory alloy (SMA) by oxidizing in H(2)O(2) solution and subsequent NaOH treatment and characterized by scanning electron microscopy, Raman spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy (XPS). The bioactivity of the film was investigated using a simulated body fluid (SBF) soaking test. A titania (TiO(2)) layer was first found on NiTi substrate after oxidized in H(2)O(2) solution, and then a porous sodium titanate (Na(2)TiO(3))/titania film with many Ti--OH groups and a trace of Ni(2)O(3) was formed by the reaction of partial TiO(2) phase with NaOH solution. After immersion in SBF for 12 h, apatite was observed to nucleate and grow on the film. With longer soaking time, more apatite appeared on its surface but our control experiments didn't reveal any apatite formation on the chemically polished NiTi SMA, which indicates the bioactivity of NiTi implants could be improved by the formation of the bioactive film. Moreover, XPS depth profiles of O, Ni, Ti, and Na show the bioactive film possesses a smooth graded interface structure to NiTi substrate, which is in favor of sufficient mechanical stability of apatite layer by subsequent deposition in SBF.

Biocompatible Materials↗

PubMed2006

Bioactive glass/polymer composite materials with mechanical properties matching those of cortical bone.

Stress shielding resulting from mismatch in dynamic mechanical properties contributes to the reduced stability of osseous implants. Our objective was to develop biocompatible composites having mechanical properties similar to those of cortical bone. Polymers of urethane dimethacrylate (UDMA) and 2-hydroxyethyl methacrylate (HEMA, 0-20%) and composites containing bioactive glass particles (70% SiO(2), 25% CaO, and 5% P(2)O(5)), with or without silane treatment were prepared. Young's moduli of composites containing silane-treated glass (16 GPa) were significantly greater than those of composites containing untreated glass (12-13 GPa) or of unfilled polymers (5-6 GPa). Bioactive glass reduced water sorption by the composites and incorporation of silane-treated glass prevented HEMA-induced increases in water sorption. Osteoblast-like cells attached equally well to UDMA polymer and composite containing silane-treated bioactive glass. Thus, silane treatment improved the mechanical properties of bioactive glass composites without compromising biocompatibility. This material has a Young's modulus comparable to that of cortical bone. Therefore, silane-treated bioactive glass composites, when used as implant or cement materials, would reduce stress shielding and improve implant stability.

Animals↗

PubMed2003

PMMA-based bioactive cement: effect of CaF2 on osteoconductivity and histological change with time.

A new bioactive bone cement (designated GBC), which is a polymethyl methacrylate- (PMMA-) based composite consisting of bioactive glass beads as an inorganic filler and high-molecular-weight PMMA (hPMMA) as an organic matrix, has been developed. The bioactive glass beads consist of MgO-CaO-SiO(2)-P(2)O(5)-CaF(2) glass. The purpose of the present study was to evaluate the effect of CaF(2) on osteoconductivity and to evaluate the degree of cement degradation with time. Three different types of cement were prepared. GBC(F +), which has been previously described, consisted of CaF(2)-containing bioactive glass beads and hPMMA. GBC(F -) consisted of CaF(2)-free bioactive glass beads and hPMMA. The third cement was hPMMA itself (as a reference material). These three types of cement were packed into the intramedullary canals of rat tibiae to evaluate osteoconductivity, as determined by an affinity index calculated as the length of bone in direct contact with the cement surface expressed as a percentage of the total length of the cement surface. Rats were killed at 4, 8, 25, and 52 weeks after implantation, and the affinity index was calculated for each type of cement at each time point. Histologically, new bone had formed along the surface of both GBC(F +) and GBC(F -) within 4 weeks, whereas hPMMA had little contact with bone, and an intervening soft tissue layer between bone and cement was detected. No significant difference in affinity index was found between GBC(F +) and GBC(F -) at any of the time points studied, although GBC(F -) showed higher affinity indices than GBC(F +) at 8, 25, and 52 weeks. The affinity indices for GBC(F +) and GBC(F -) were significantly higher than those for hPMMA at all time points. With GBC(F +) and GBC(F -), significant increases in the affinity indices were found as the implantation period increased, and the affinity index values at 52 weeks reached more than 70%. In hPMMA, no significant increase in affinity index was observed up to 52 weeks, and the value at 52 weeks was less than 30%. Although no significant difference in affinity index was found between GBC(F +) and GBC(F -), GBC(F -) is conclusively better than GBC(F +) because diseases such as chronic fluorosis might be caused by CaF(2)-containing glass beads. Regarding the cement degradation of both GBC(F +) and GBC(F -), the degree of the degradation at 25 weeks was the same as that at 52 weeks. Therefore, the cement degradation does not appear to proceed rapidly. Further studies are needed to better understand the degradation process.

Animals↗

PubMed2003

Composite surgical sutures with bioactive glass coating.

A processing method was developed to coat polyglactin 910 (Vicryl) sutures with bioactive glass powder (45S5 Bioglass). High reproducibility and homogeneity of the coating in terms of microstructure and thickness along the suture length were achieved. Bioglass-coated sutures exhibited a high level of chemical reactivity in simulated body fluid (SBF), indicating their bioactive behavior. This was evident by the prompt formation of hydroxyapatite (HA) crystals on the surface after only 7 days of immersion in SBF. These crystals grew to form a thick HA layer (15 microm thickness) after 3 weeks in SBF. The tensile strength of the sutures was tested before and after immersion in SBF in order to assess the effect of the bioactive glass coating on suture degradation. The tensile strength of composite sutures was lower than that of as-received Vicryl sutures, 385 and 467 MPa, respectively. However, after 28 days of immersion in SBF the residual tensile strengths of coated and uncoated sutures were similar (83 and 88 MPa, respectively), indicating no negative effect of the HA layer formation on the suture strength. The effect of bioactive glass coating on the polymer degradation is discussed. The developed bioactive sutures represent interesting materials for applications in wound healing, fabrication of fibrous three-dimensional scaffolds for tissue engineering, and reinforcement elements for calcium-phosphate temporary implants.

Body Fluids↗

PubMed2007

Effect of biopassive and bioactive surface-coatings on the hemocompatibility of membrane oxygenators.

Postoperative complications associated with cardiopulmonary bypass (CPB) surgery and extracorporeal circulation (ECC) procedures are still a major clinical issue. Improving the hemocompatibility of blood contacting devices used for ECC procedures may ameliorate various postpump syndromes. In a simulated CPB model using human blood, we investigated the hemocompatibility, fibrinogen adsorption, and platelet receptor (GPIIb-IIIa) binding capacity of surface-modified membrane oxygenators (Jostra Quadrox). Three groups were compared: (i) biopassive protein coatings (SafeLine), (ii) bioactive heparin coatings (BioLine), and (iii) noncoated controls. During the 2 h recirculation period, plasma concentrations of activation markers for platelets (beta-thromboglobulin), inflammation (elastase), complement (C5a), and coagulation (prothrombin fragment 1+2, thrombin-antithrombin III) were lower in the groups with biopassive and bioactive coatings compared to the noncoated group (p < 0.01). These parameters did not significantly differ between the two surface-coated groups, except for complement activation: C5a levels were higher in the biopassive group compared to the bioactive group (p < 0.01). Moreover, surface-coated oxygenators showed less fibrinogen adsorption, GPIIb-IIIa binding, and platelet/leukocyte adhesion (p < 0.01). We assume that fewer fibrinogen and platelet receptor molecules bound to the surface-coated oxygenator surfaces results in fewer platelet adhesion and activation, which will significantly contribute to the improved hemocompatibility of the biopassive and bioactive oxygenators. Our results suggest that the application of bioactive oxygenators (BioLine) during CPB surgery may reduce postoperative complications for the patient more effectively than biopassive oxygenators (SafeLine).

Adsorption↗

PubMed2000

Neural network methods for identification and optimization of quantum mechanical features needed for bioactivity.

This paper presents a new approach to the discovery and design of bioactive compounds. The focus of this application will be on the analysis of enzymatic inhibitors. At present the discovery of enzymatic inhibitors for therapeutic use is often accomplished through random searches. The first phase of discovery is a random search through a large pre-fabricated chemical library. Many molecules are tested with refined enzyme for signs of inhibition. Once a group of lead compounds have been discovered the chemical intuition of biochemists is used to find structurally related compounds that are more effective. This step requires new molecules to be conceived and synthesized, and it is the most time-consuming and expensive step. The development of computational and theoretical methods for prediction of the molecular structure that would bind most tightly prior to synthesis and testing, would facilitate the design of novel inhibitors. In the past, our work has focused on solving the problem of predicting the bioactivity of a molecule prior to synthesis. We used a neural network trained with the bioactivity of known compounds to predict the bioactivity of unknown compounds. In our current work, we use a separate neural network in conjunction with a trained neural network in an attempt to gain insight as to how to modify existing compounds and increase their bioactivity.

Enzyme Inhibitors↗

PubMed1994

Effect of glass bioactivity on new bone development induced by demineralized bone matrix in a rat extraskeletal site.

The effects of two kinds of bioactive glass and two kinds of phosphate-free glass on new bone development induced by demineralized bone matrix (DBM) were studied in the rat abdominal muscle pouch model. After 8 weeks' implantation histomorphometric analysis revealed that the amount of new bone in DBM combined with bioactive glass was comparable to DBM without bioactive glass. DBM grafts combined with phosphate-free glass showed significantly less new bone formation. Scanning electron microscopic examination confirmed that new bone bonded to the surface of bioactive glass. The release of ions from the glass seemed to slow down after new bone had bonded to it. Exclusion of phosphate from a bioactive glass resulted in loss of ability to develop the Ca,P-rich surface layer needed for bone bonding.

Animals↗

PubMed1999

Initiation of an Aquaculture of Sponges for the Sustainable Production of Bioactive Metabolites in Open Systems: Example, Geodia cydonium.

Among Metazoa, sponges (phylum Porifera) are the richest source for different bioactive compounds. The availability of the raw material is, however, restricted. To obtain enough of the bioactive compounds for application in human therapy, sponges have to be cultured in in vitro systems. One technique for the establishment of a long-term cell culture from sponges has recently been elaborated. Here, we present a procedure to cultivate tissue samples from sponges in an open system. The species Geodia cydonium, which produces bioactive compounds, has been selected. Tissue samples of approximately 10 g were attached to the bottoms of cultivation trays. After 2 to 3 days, the tissue samples formed a robust contact with the metal support. Subsequently, sets of trays, called tray batteries, either remained in huge aquaria at the Center for Marine Research or were transferred to the vicinity of a fish and mussel farm. The growth rates of the samples remained unchanged within the first month; however, after 3 and 6 months, they increased to 147% and 189%, respectively. In parallel, extracts were prepared from the tissue samples and tested for cytotoxicity in a mouse lymphoma cell assay system. Extracts from cultured tissue initially had a low inhibitory potency; however, after cultivation for 3 or 6 months, values comparable to those of extracts from sponges taken from the biotope were found. In addition, a molecular marker was applied to document the response (health state) of the tissue and the identity of the material in culture. The CD63 molecule was chosen because the expression of this molecule in mammalian systems changes with the age of the animals. The corresponding complementary DNA was isolated from Geodia cydonium. With this probe, the level of expression in cultured tissue samples decreased immediately after starting cultivation; after a cultivation period of 6 months, however, values were similar to those found in controls. These data show that sponge species that produce bioactive compounds can be cultivated in open systems, in which they retain their potency to produce bioactive compounds as well as their health state.

Journal Article↗

PubMed2003

Structure-Activity Studies of Brassinosteroids and the Search for Novel Analogues and Mimetics with Improved Bioactivity.

A number of novel brassinosteroid analogues were synthesized and subjected to the rice leaf lamina inclination bioassay. Modified B-ring analogues included lactam, thiolactone, cyclic ether, ketone, hydroxyl, and exocyclic methylene derivatives of brassinolide. Those derivatives containing polar functional groups retained considerable bioactivity, whereas the exocyclic methylene compounds were devoid of activity. Analogues containing normal alkyl and cycloalkyl substituents at C-24 (in place of the isopropyl group of brassinolide) showed an inverse relationship between activity and chain length or ring size, respectively. The corresponding cyclopropyl and cyclobutyl derivatives were significantly more active than brassinolide and appear to be the most potent brassinosteroids reported to date. When synergized with the auxin indole-3-acetic acid (IAA), their bioactivity can be further enhanced by 1-2 orders of magnitude. The cyclopropyl derivative, when coapplied with the auxin naphthaleneacetic acid, gave a significant increase in yield of wheat in a field trial. Certain 25- and 26-hydroxy derivatives are known metabolites of brassinosteroids. All of the C-25 stereoisomers of 25-hydroxy, 26-hydroxy, and 25,26-dihydroxy derivatives of brassinolide were prepared and shown to be much less active than brassinolide. This indicates that they are likely metabolic deactivation products of the parent phytohormone. A series of methyl ethers of brassinolide was synthesized to block deactivation by glucosylation of the free hydroxyl groups. The most significant finding was that the compound where three of the four hydroxyl groups (at C-3, C-22, and C-23) had been converted to methyl ethers retained substantial bioactivity. This type of modification could, in theory, allow brassinolide or 24-epibrassinolide to resist deactivation and thus offer greater persistence in field applications. A series of nonsteroidal mimetics of brassinolide was designed and synthesized. Two of the mimetics showed significant bioactivity and one had bioactivity comparable to brassinolide, but only when formulated and coapplied with IAA. They thus represent the first nonsteroidal analogues possessing brassinosteroid activity.

Journal Article↗

PubMed2000

Tissue response to bioactive glass and autogenous bone in the rabbit spine.

Bioactive glass S53P4 and autogenous bone were used as bone graft materials in an experimental rabbit model for spinal fusion. The study focused on differences in bone formation using bioactive glass and autogenous bone as bone graft materials. Bioactive glass, a mixture of bioactive glass and autogenous bone or autogenous bone was implanted for 4 and 12 weeks at the thoracolumbar level. Undecalcified sections were prepared for histological and histomorphometric evaluation. New bone formation was seen in all implanted areas, with the bone growing from the surface of the vertebrae enclosing both glass and autogenous bone in the bone fusion mass. During the observation period, the measured amount of bone remained at the same level in the autograft group, while in the glass and the glass/autograft bone groups it increased. By 12 weeks, no significant difference in bone formation between the three groups was observable. The bone formation in two selected standardized areas at 12 weeks was 21 and 24% in the glass group, 23 and 28% in the glass/autograft bone group and 27 and 26% in the autograft bone group. We consider bioactive glass as a potential bone graft material in experimental spinal fusion.

Animals↗

PubMed2006

Osmotic-driven release kinetics of bioactive therapeutic proteins from a biodegradable elastomer are linear, constant, similar, and adjustable.

PURPOSE: The aim of the study is to determine whether a biodegradable elastomeric device that uses an osmotic pressure delivery mechanism can release different therapeutic proteins at a nearly constant rate in nanomolar concentrations with high bioactivity, given the same formulation conditions. Vascular endothelial growth factor (VEGF) and interleukin-2 (IL-2) were embedded in the device as sample therapeutic proteins, and their release and bioactivity were compared to that achieved previously with interferon-gamma (IFN-gamma). METHODS: A photo-cross-linkable biodegradable macromer consisting of acrylated star(epsilon-caprolactone-co-D,L-lactide) was prepared. VEGF, IL-2, and IFN-gamma were co-lyophilized with serum albumin and trehalose at different ratios and were then embedded into the elastomer by photo-cross-linking the lyophilized particles in a macromer solution. The protein mass and the bioactivity in the release supernatant were measured by enzyme-linked immunosorbent and cell-based assays. RESULTS: VEGF, IL-2, and IFN-gamma were released at the same, nearly constant rate of 25.4 ng/day for over 18 days. Using the optimum elastomer formulation, the release profiles of the proteins were essentially identical, and their rates were linear and constant. Cell-based bioactivity assays showed that 70 and 88% of the released VEGF and IL-2, respectively, were bioactive. The rate of protein release can be adjusted by changing the trehalose loading concentration in the elastomer matrix without altering the linear nature of the protein release kinetics. The elastomeric device degraded in PBS buffer within 85 days. CONCLUSIONS: The elastomer formulation shows promising potential as a sustained protein drug delivery vehicle for local delivery applications.

Cells, Cultured↗

PubMed1992

Increased bioactive luteinizing hormone levels in postmenopausal women with endometrial cancer.

OBJECTIVE: The purpose of our study was to investigate the secretion of immunoactive and bioactive luteinizing hormone in postmenopausal women with endometrial cancer. STUDY DESIGN: Seventeen postmenopausal women with endometrial cancer and nine without cancer were studied. Blood samples were collected at 15-minute intervals for 360 minutes. All samples were assayed for bioactive luteinizing hormone by rat interstitial cell testosterone assay and for immunoactive luteinizing hormone by radioimmunoassay. Serum pooled from 6-hour sampling was assayed for follicle-stimulating hormone, total estradiol, unbound estradiol, and estrone. RESULTS: Patients with endometrial cancer had significantly (p < 0.01) higher bioactive luteinizing hormone levels (mean +/- SE 276 +/- 26 IU/L) as compared with those of control women (144 +/- 18 IU/L). Bioactive/immunoactive ratios of luteinizing hormone were significantly higher (p < 0.01) in women with cancer (5.8 +/- 0.7) than in those without cancer (2.5 +/- 0.5). There was a significant (p < 0.001) positive correlation (r = 0.582) between unbound estradiol levels and bioactive luteinizing hormone concentrations. CONCLUSIONS: There is an increase in bioactive luteinizing hormone secretion in postmenopausal women with endometrial cancer. This could lead to an increase in ovarian androgen production resulting in increased prehormone availability for estrogen formation from peripheral conversion.

Aged↗

PubMed1991

Bioactivation of xenobiotics by prostaglandin H synthase.

Prostaglandin H synthase (PHS) catalyzes the oxidation of arachidonic acid to prostaglandin H2 in reactions which utilize two activities, a cyclooxygenase and a peroxidase. These enzymatic activities generate enzyme- and substrate-derived free radical intermediates which can oxidize xenobiotics to biologically reactive intermediates. As a consequence, in the presence of arachidonic acid or a peroxide source, PHS can bioactivate many chemical carcinogens to their ultimate mutagenic and carcinogenic forms. In general, PHS-dependent bioactivation is most important in extrahepatic tissues with low monooxygenase activity such as the urinary bladder, renal medulla, skin and lung. Mutagenicity assays are useful in the detection of compounds which are converted to genotoxic metabolites during PHS oxidation. In addition, the oxidation of xenobiotics by PHS often form metabolites or adducts to cellular macromolecules which are specific for peroxidase- or peroxyl radical-dependent reactions. These specific metabolites and/or adducts have served as biological markers of xenobiotic bioactivation by PHS in certain tissues. Evidence is presented which supports a role for PHS in the bioactivation of several polycyclic aromatic hydrocarbons and aromatic amines, two classes of carcinogens which induce extrahepatic neoplasia. It should be emphasized that the toxicities induced by PHS-dependent bioactivation of xenobiotics are not limited to carcinogenicity. Examples are given which demonstrate a role for PHS in pulmonary toxicity, teratogenicity, nephrotoxicity and myelotoxicity.

Animals↗

PubMed1994

delta 9-Tetrahydrocannabinol (THC) modulates IL-1 bioactivity in human monocyte/macrophage cell lines.

We have previously observed that delta 9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, increased supernatant interleukin-1 (IL-1) bioactivity in cultures of mouse resident peritoneal macrophages stimulated with lipopolysaccharide (LPS). In this study, experiments were performed to determine whether THC treatment similarly affected phagocytes of human origin. The results showed that THC increased the levels of supernatant IL-1 bioactivity of two human monocytic cell lines, but only if the cells were differentiated with phorbol myristate acetate. Undifferentiated cells displayed decreased IL-1 bioactivity in response to THC. However, under conditions in which THC augmented supernatant IL-1 bioactivity from THP-1 cells, ELISA studies showed that the levels of IL-1 alpha and IL-1 beta were unchanged and decreased, respectively. Furthermore, supernatant interleukin-6 (IL-6) levels were decreased, but tumor necrosis factor (TNF-alpha) levels were increased by THC treatment. These results show that THC treatment modulates cytokine production and/or release by mouse and human macrophages and the drug effects on IL-1-like bioactivity in the supernatants of the human THP-1 cells are due to increased levels of other cytokines, such as TNF-alpha, rather than IL-1 itself.

Animals↗

PubMed1990

Bioactivation of 3-methylindole by isolated rabbit lung cells.

3-Methylindole (3MI) is a pneumotoxin that causes selective lung lesions indicative of Clara cell and alveolar epithelial cell damage in ruminants and rodents. The present study examined the cytotoxicity of 3MI to isolated rabbit Clara cells, type II alveolar epithelial cells, and alveolar macrophages. 3MI produced a dose-dependent cytotoxicity to Clara cells detectable within 1 hr of incubation at 37 degrees C which reached a maximum at 3 hr. Concentrations of 0.25 and 0.5 mM 3MI were cytotoxic to Clara cells, while type II and alveolar macrophages required 1 mM 3MI before cytotoxicity was observed. The cytochrome P450 suicide substrate inhibitor, 1-aminobenzotriazole, inhibited 3MI-induced cytotoxicity in Clara cells, type II cells, and alveolar macrophages. These observations were consistent with a cytochrome P450-mediated bioactivation of 3MI to a toxic intermediate. Studies with a trideuteromethyl analog of 3MI demonstrated a much reduced cytotoxicity to Clara cells as well as to type II cells, and macrophages. The deuterium isotope effect suggested that C-H bond breakage at the 3-methyl group is a requisite oxidative transformation in the bioactivation of 3MI to a selective lung cell cytotoxin. The selectivity of cellular cytotoxicity is probably associated with higher rates of bioactivation by Clara cell cytochrome P450 monooxygenases compared to those of type II cells and macrophages. These studies demonstrate that 3MI is bioactivated in isolated pulmonary cells without the intervention of other organs and that bioactivation requires functional cytochrome P450 enzymes.

Animals↗