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Biomedical subjects

J Rabovsky

Publications and source records attributed to J Rabovsky.

18 recordsLinked to original sources
PubMed2001

A health risk benchmark for the neurologic effects of styrene: comparison with NOAEL/LOAEL approach.

Benchmark dose (BMD) analysis was used to estimate an inhalation benchmark concentration for styrene neurotoxicity. Quantal data on neuropsychologic test results from styrene-exposed workers [Mutti et al. (1984). American Journal of Industrial Medicine, 5, 275-286] were used to quantify neurotoxicity, defined as the percent of tested workers who responded abnormally to > or = 1, > or = 2, or > or = 3 out of a battery of eight tests. Exposure was based on previously published results on mean urinary mandelic- and phenylglyoxylic acid levels in the workers, converted to air styrene levels (15, 44, 74, or 115 ppm). Nonstyrene-exposed workers from the same region served as a control group. Maximum-likelihood estimates (MLEs) and BMDs at 5 and 10% response levels of the exposed population were obtained from log-normal analysis of the quantal data. The highest MLE was 9 ppm (BMD = 4 ppm) styrene and represents abnormal responses to > or = 3 tests by 10% of the exposed population. The most health-protective MLE was 2 ppm styrene (BMD = 0.3 ppm) and represents abnormal responses to > or = 1 test by 5% of the exposed population. A no observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) analysis of the same quantal data showed workers in all styrene exposure groups responded abnormally to > or = 1, > or = 2, or > or = 3 tests, compared to controls, and the LOAEL was 15 ppm. A comparison of the BMD and NOAEL/LOAEL analyses suggests that at air styrene levels below the LOAEL, a segment of the worker population may be adversely affected. The benchmark approach will be useful for styrene noncancer risk assessment purposes by providing a more accurate estimate of potential risk that should, in turn, help to reduce the uncertainty that is a common problem in setting exposure levels.

Air Pollutants, Occupational↗
PubMed1995

Biogenic amorphous silica.

Biogenic amorphous silica (BAS) is a natural constituent of living matter (eg, unicellular organisms and crop plants). Diatoms, whose siliceous remains are the geologic precursors to diatomaceous earth, actively process soluble silica into BAS. In some plants, a portion of the BAS exists externally as pointed or irregularly shaped fibers. Although silica-related adverse health effects are usually attributed to crystalline forms, such effects could occur as a result of exposure to BAS at high temperatures (above 800 degrees C), where crystalline silica, a known human toxicant is formed. BAS fibers from food crops can be ingested and lead to adverse health effects due to irritative processes. Airborne BAS fibers from rice can be inhaled during burning or incineration. Fibrous or nonfibrous BAS can adsorb toxic organic compounds and facilitate their entry into the lung. Recommendations for research are suggested to address the issue of potential health effects due to exposure to BAS.

Agriculture↗
PubMed1991

Cytochrome P-450-dependent metabolism in alveolar type II epithelial cells: modulation by platelet-activating factor.

Platelet-activating factor (PAF), an ether lipid mediator released from activated pulmonary phagocytes, was evaluated for its ability to affect cytochrome P-450-dependent activities in isolated rat alveolar type II cells. The data indicate that at non-toxic doses, PAF caused an increase in beta-naphthoflavone (BNF) inducible/alpha-naphthoflavone (ANF) sensitive ethoxyphenoxazone deethylase (EtOPx'ase) activity. At high concentrations of PAF, inhibition of both EtOPx'ase and metyrapone (MP) sensitive benzyloxyphenoxazone debenzylase (BzOPx'ase) activities and aggregation of type II cells were observed. The PAF analogs, lyso-PAF and enantio-PAF, exhibited actions similar to those observed with PAF. PAF-induced enhancement of EtOPx'ase activity required the presence of intact cells, whereas at high PAF concentrations decreased enzyme activities were observed in both intact cell and sonicated cell preparations. The data thus suggest that xenobiotic metabolism in alveolar type II cells can be modified by an inflammatory mediator, such as PAF, produced by alveolar phagocytes.

Animals↗
PubMed1990

Lung cytochrome P450-dependent benzyloxyphenoxazone debenzylase and ethoxyphenoxazone deethylase activities in total microsomal and isolated alveolar type II cells: responses to changes in assay conditions with special reference to non-linear dependence at low enzyme concentration.

1. Responses of cytochrome P450-dependent ethoxyphenoxazone deethylase (EtOPx'ase) and benzyloxyphenoxazone debenzylase (BzOPx'ase) activities to changes in assay conditions were measured in total microsomal and isolated alveolar type II (tII) cells from rats pretreated with beta-naphthoflavone. 2. Whereas microsomal EtOPx'ase activity was unaffected by storage at -80 degrees C for up to 4 months, BzOPx'ase activity began to decline after only 1 month. 3. The microsomal and type II activities were unaffected by changes in pH (7.2-8.0) or salt content. 4. The type II activities increased after sonication 2.3-2.7-fold or in the presence of 10 microM dicumarol 1.7-1.9-fold. 5. Type II BzOPx'ase was sensitive to metyrapone (MP) whereas EtOPx'ase was sensitive to alpha-naphthoflavone (ANF). I50 values for the tII activities were calculated as: 0.63 microM--MP (BzOPx'ase), 80 microM--MP (EtOPx'ase), 0.024 microM--ANF (EtOPx'ase). At the highest concentration of ANF (10 microM), 50% inhibition tII BzOPx'ase was not observed. The results were similar to those obtained with the total lung microsomal fraction. 6. Microsomal and tII BzOPx'ase activities exhibited non-linear dependence at low enzyme concentration. Linearity was restored by 0.5 mM dimyristoylphosphatidylcholine.

Animals↗
PubMed1990

Platelet-activating factor-induced aggregation of rat alveolar macrophages.

Isolated rat alveolar macrophages aggregate in the presence of PAF in a dose- and cell-dependent manner. Saturation was achieved at 80 microM PAF. The response was increased linearly with cell number up to a concentration of 3 x 10(6) cells/ml, but decreased at higher cell concentrations. The stereoisomer, enantio-PAF, and the C2-acetyl hydrolyzed product, lyso-PAF, each caused aggregation of isolated rat alveolar macrophages in a manner similar to that for PAF. The PAF-induced aggregation of alveolar macrophages may be mediated through non-specific binding sites and may represent a toxic response to relatively high levels of PAF that released at localized sites.

Animals↗
PubMed1989

Cytochrome P450-dependent alkoxyphenoxazone dealkylase activity in rat alveolar type II cells: effect of pretreatment with beta-naphthoflavone.

Cytochrome P450-dependent alkoxyphenoxazone dealkylase activity was measured in alveolar type II cells from control and beta-naphthoflavone (ip) treated-rats. Type II cells were isolated from collagenase/elastase-digested lung tissue and purified by centrifugal elutriation. The specificity of the cytochrome P450-dependent activity towards four alkoxyphenoxazones (methoxy-, ethoxy-, pentoxy-, and benzyloxyphenoxazone) was measured under conditions that minimized interference by cytosolic conjugating- and NADPH-dependent quinone reductase activities. Ethoxyphenoxazone dealkylase activity was induced 17-fold following beta-naphthoflavone treatment and was further characterized by its kinetic parameters and sensitivities toward in vitro inhibitors (Km(app) = 0.20 microM, Vmax = 1.74 pmoles resorufin min-1 (10(6) cells)-1 10(6) cells; I50 (alpha-naphthoflavone) = 0.025 microM, and I50 (metyrapone) = 72 microM). beta-Naphthoflavone pretreatment of the rats did not result in statistically significant changes in methoxy-, pentoxy-, or benzyloxyphenoxazone dealkylase activity of alveolar type II cells, although, a trend towards decrease activity was observed for benzyloxyphenoxazone. beta-Naphthoflavone pretreatment had no effect on oxygen consumption or trypan blue exclusion in alveolar type II cells and macrophage ethoxyphenoxazone dealkylase and benzyloxphenoxazone dealkylase activities were not affected by the beta-naththoflavone pretreatment. The results show that exposure to beta-naphthoflavone resulted in an increase in type II cell cytochrome P450-dependent ethoxyphenoxazone dealkylase activity but not in other alveolar type II cell or macrophage alkoxyphenoxazone dealkylase activities or in parameters that monitor viability and cell wall integrity.

Animals↗
PubMed1989

Nonideal behavior of alkoxyphenoxazone compounds (cytochrome P-450 substrates) in aqueous solution.

Spectral properties of the cytochrome P-450 substrates, methoxy-, ethoxy-, pentoxy-, and benzyloxyphenoxazone (MeOPx, EtOPx, PeOPx, and BzOPx, respectively) were investigated from 350 to 600 nm in ethanol and aqueous buffer. In ethanol, each alkoxyphenoxazone displayed a lambda max at 460 nm and a shoulder around 390 nm. Extinction coefficients (EmM) in ethanol were calculated as MeOPx, 20.5; EtOPx, 20.4; PeOPx, 24.7; and BzOPx, 22.4. In aqueous buffer, only MeOPx obeyed the Lambert-Beer law (lambda max = 480 nm, EmM = 22.1). Three substrates, EtOPx, PeOPx, and BzOPx, displayed anomalous behavior in aqueous solution, wherein the lambda max shifted to lower wavelengths (480-430 nm) and EmM (apparent) decreased as the alkoxyphenoxazone concentration increased. This behavior was dependent on the side chain, and the concentrations at which the spectral changes took place were estimated as: BzOPx, 2 microM; PeOPx, 5 microM; EtOPx, 17 microM; and MeOPx, greater than 20 microM. The blue shift and decreased EmM (apparent) observed for PeOPx at high concentration in aqueous buffer was reversed at high temperature. Unlike EtOPx, PeOPx, and BzOPx, and like MeOPx, hydroxyphenoxazone (resorufin) and unsubstituted phenoxazone obeyed the Lambert-Beer law in aqueous buffer and ethanol. The data suggest that the pentoxy and benzyloxy substituents facilitated a self-association process among the phenoxazones in aqueous solution. The data further show that aqueous solutions should be avoided when spectral data are used to determine alkoxyphenoxazone concentrations.

Chemical Phenomena↗
PubMed1989

The in vitro effects of alkanes, alcohols, and ketones on rat lung cytochrome P450-dependent alkoxyphenoxazone dealkylase activities.

The sensitivities of cytochrome P450 (EC 1.14.14.1)-dependent benzyloxy- and ethoxyphenoxazone dealkylase (BzOPh'ase and EtOPh'ase, respectively) activities towards a series of aliphatic hydrocarbons were measured in the microsomal fraction of lung obtained from beta-naphthoflavone-treated rats. The unsubstituted hydrocarbons were straight-chain (n-hexane through n-undecane) and branch-chain (eight carbons). The substituted compounds were alcohols and ketones of hexane and octane. The data are expressed as I50 values, i.e. the hydrocarbon concentration required to cause 50% decrease in the rate of enzyme-catalyzed product (resorufin) formation. The unsubstituted aliphatic hydrocarbons exhibited I50 values towards BzOPh'ase from 0.76 microM (2,5-dimethylhexane) to 8.8 microM (n-hexane). The lung EtOPh'ase activity was insensitive towards the tested unsubstituted aliphatic hydrocarbons. When the alcohols and ketones of hexane and octane were tested against lung BzOPh'ase activity, I50 values ranged from 16 microM (1-octanol) to 4.8 mM (2,5-hexanedione). Lung EtOPh'ase activity exhibited some sensitivity towards the alcohols and ketones, and I50 values ranged from 0.52 mM (4-octanol) to 40.5 mM (2-hexanol). The data show rat lung BzOPh'ase and EtOPh'ase activities are differentially sensitive towards the selected unsubstituted aliphatic hydrocarbons and corresponding alcohols and ketones. The difference in sensitivities may reflect different requirements for an adventitious interaction between a hydrocarbon and enzyme active site.

Alcohols↗
PubMed1988

The alveolar type II epithelial cell: a multifunctional pneumocyte.

The epithelial surface of the alveoli is composed of alveolar type I and type II cells. Alveolar type I cells comprise 96% of the alveolar surface area. These cells are extremely thin, thus, minimizing diffusion distance between the alveolar air space and pulmonary capillary blood. Type II cells are spherical pneumocytes which comprise only 4% of the alveolar surface area, yet they constitute 60% of alveolar epithelial cells and 10-15% of all lung cells. Four major functions have been attributed to alveolar type II cells: (1) synthesis and secretion of surfactant; (2) xenobiotic metabolism; (3) transepithelial movement of water; and (4) regeneration of the alveolar epithelium following lung injury. Therefore, alveolar type II cells play important roles in normal pulmonary function and in the response of the lung to toxic compounds which may cause lung damage. Techniques have now been developed to isolate and purify alveolar type II epithelial cells from lung tissue. Such cellular preparations afford bioassay systems to monitor the effects of occupational or environmental pollutants on alveolar pneumocytes and should yield important information concerning the etiology of pulmonary disease in the alveolar region of the lung.

Animals↗
PubMed1987

The non-linear dependence of cytochrome P450 activity at low microsome concentration.

A non-linear decrease in the activity of cytochrome P450-dependent (P450) ethoxyphenoxazone deethylase was observed with intact rat liver and lung microsomal fractions, although all components of the P450 complex were present. Activity was restored by adding pre-heated microsomal membranes or synthetic phospholipid, or by concentrating the diluted preparation. Aqueous dilution of the microsomal fraction resulted in altered Vmax values, whereas Km(app) values (0.2 microM) were only slightly changed. The results are discussed in terms of the relationship between cytochrome P450 action in model systems and in native microsomal membranes.

Animals↗
PubMed1987

Cytochrome P450-dependent alkoxyphenoxazone dealkylase activities in lung microsomes from untreated and beta-naphthoflavone-treated rats: effect of in vitro inhibitors.

The reactivities of four alkoxyphenoxazone derivatives toward cytochrome P450-dependent monooxygenase activity were studied in lung microsomes from control and beta-naphthoflavone (BNF)-treated rats. Ethoxyphenoxazone (EtOPh)- and methoxyphenoxazone (MeOPh)-dealkylases were induced by beta NF (16- and 3.9-fold respectively), whereas benzyloxyphenoxazone (BzOPh)- and pentoxyphenoxazone (PeOPh)-dealkylase activities were unchanged after pre-treatment with beta NF. The specific activities of BzOPh'ase from control- and beta NF-treated rats and EtOPh'ase from beta NF-treated rats were sufficiently high (214-560 pmoles resorufin per min per mg protein) for routine biochemical studies. Each differed in its sensitivity toward the in vitro inhibitors, alpha-naphthoflavone (ANF) and metyrapone (MP). In lung microsomes from beta NF-treated rats the I50 (MP) = 7.6 X 10(-5) M for EtOPh'ase and 1.0 X 10(-6) M for BzOPh'ase. I50 (ANF) = 3.8 X 10(-8) M for EtOPh'ase. I50 (ANF) for BzOPh'ase could not be determined; at the highest concentration of ANF (10(-3) M), 50% inhibition was not observed. The presence of high levels of two distinct forms of lung microsomal P450-dependent alkoxyphenoxazone dealkylases, BzOPh'ase from untreated and beta NF-treated rats and EtOPh'ase from beta NF-treated rats, will be useful for studies on specific P450-xenobiotic interactions in rat pulmonary tissue.

Animals↗
PubMed1986

Influenza virus-induced alterations of cytochrome P-450 enzyme activities following exposure of mice to coal and diesel particulates.

We have investigated a relationship between two detoxication systems, metabolic detoxication through the cytochrome P-450 (P-450) pathway and resistance to infection through interferon (IFN), in mice infected with influenza virus following exposure to coal dust (CD) and diesel exhaust (DE) particulates. Mice were exposed by inhalation to filtered air (FA; control), CD, or DE for 1 month and then inoculated intranasally (IN) with influenza virus. During infection, 7-ethoxycoumarin deethylase (7ECdeEt'ase) and ethylmorphine demethylase (EMdeMe'ase) (monooxygenases), and NADPH cytochrome c reductase (NADPH c red'ase) were measured in liver microsomes. Temporal patterns of enzyme activities were observed with control animals. EMdeMe'ase and NADPH c red'ase exhibited peak values at Day 4 postinfection (27.6 and 482 nmole/min/mg protein, respectively), compared to initial activities (9.1 and 307 nmole/min/mg protein, respectively). 7ECdeEt'ase activity decreased between Days 1-3 postvirus infection and thereafter returned to the original value (1.7 nmole/min/mg protein). When the mice were first exposed to CD or DE particulates for 1 month prior to influenza infection, changes in enzyme temporal patterns were observed. The increased EMdeMe'ase activity at Day 4 was not observed in mice exposed to CD and was reduced in mice exposed to DE. Preexposure to either particulate resulted in the abolition of the increased Day 4 activity of NADPH c red'ase. The 7ECdeEt'ase postinfection temporal pattern was not affected by a preexposure to either particulate. Estimates of the enzyme activities after the 1-month exposure to FA, CD, or DE but before virus infection indicated no changes due to particulate exposure alone. Under these conditions of particulate exposure and virus infection, serum IFN levels in the mice used in this study peaked at Days 4-5 and were unaffected by the 1-month preexposure to CD or DE (Hahon et al., (1985). The data suggest the relationship that exists between metabolic detoxication and resistance to infection in normal mice was altered during a short-term preexposure to CD or DE.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

In vitro effects of straight-chain alkanes (n-hexane through n-dodecane) on rat liver and lung cytochrome P-450.

To evaluate the effect of straight-chain alkanes on normal detoxication reactions, we studied the in vitro effect of the homologous series n-hexane through n-dodecane on two cytochrome P-450 (EC 1.14.14.1) enzyme activities. Benzo[a]pyrene hydroxylase (BaPOHase) and 7-ethoxycoumarin deethylase activities were measured in liver and lung microsomes of control and beta-naphthoflavone-treated rats. In the presence of 2 mM n-hexane through n-dodecane, liver BaPOHase activity decreased from 67% of control with n-dodecane to 21% of control with octane. Lung benzo[a]pyrene hydroxylase was insensitive to all tested alkanes at 2 mM. In the presence of 2 mM alkanes, liver 7-ethoxycoumarin deethylase activity decreased from 73% of control with n-octane to 28% with n-octane. Lung 7-ethoxycoumarin deethylase was also sensitive to the alkane series. In the presence of 2 mM alkane the greatest effect was obtained with n-octane and represented a 56% loss in activity. Alkane concentration-dependence measurements showed 0.02-0.20 mM as the sensitive region of the curve for n-octane with maximal loss of activity achieved at 0.20 mM. Liver ethoxycoumarin deethylase activity from beta-naphthoflavone-treated rats was less sensitive towards the reactive alkane, n-octane, than the activity from control rats. Double-reciprocal-plot analysis revealed the maximal velocity (Vmax) was decreased in the presence of 0.2 mM n-octane. Hence this hydrocarbon did not exert its effect solely as an alternate substrate. The data show the n-alkanes, n-hexane through n-dodecane, interfered with a normal detoxication pathway in a manner that was chainlength-dependent, tissue-specific, and dependent on the preexposure history of the animal.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1984

Chronic inhalation of diesel exhaust and coal dust: effect of age and exposure on selected enzyme activities associated with microsomal cytochrome P-450 in rat lung and liver.

Male Fisher-344 rats were exposed by inhalation to low levels of diesel exhaust and coal dust, alone or in combination, or to filtered air, 7 h/d, 5 d/wk for 24 mo. Cytochrome P-450-associated benzo[a]pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 mo. Age-related changes in enzyme activities were observed, but they were not altered by the exposures. When the data were adjusted for age, only one difference was observed. Lung benzo[a]pyrene hydroxylase activity in rats exposed to diesel exhaust and coal dust in combination was lower than that in animals exposed to coal dust alone (2.8 versus 4.4 pmol/min X mg protein). Neither value, however, differed significantly from the filtered-air controls, and no differences were observed in the other lung and liver activities. The data suggest exposure of the rats to diesel exhaust and/or coal dust had little or no effect on the selected lung and liver cytochrome P-450 activities under the conditions of the experiment.

Age Factors↗
PubMed1984

Low-dose chronic inhalation of diesel exhaust and/or coal dust by rats: effect of age and exposure on lung and liver cytochrome P-450.

Rats were exposed by inhalation to low levels of diesel exhaust and/or coal dust, seven hours/day, five days/week for 24 months. Cytochrome P-450-associated benzo[a]pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 months. When data were analysed across all time intervals and adjusted for age, lower benzo[a]pyrene hydroxylase activity was observed in lung microsomes from rats exposed to diesel exhaust plus coal dust than in those exposed to coal dust alone. Data are discussed in terms of interaction between diesel exhaust and coal dust and effect of infectious agents.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

A comparison of the effect of two bovine serum albumin preparations on benzo(alpha)pyrene hydroxylase in rat liver and lung microsomes.

One of two commercial bovine serum albumin preparations caused decreases in rat liver and lung microsomal benzo(alpha)pyrene hydroxylase activities when measured by the fluorescence assay. The decreased activities were not due to a decreased recovery of a reaction product, 3-hydroxybenzo (alpha)pyrene, the presence of unmasked fatty acid binding sites or decreased content of cytochrome P450. The decreased enzyme activity may be due to a component present in the preparation. The results indicate that bovine serum albumin preparations should be carefully checked before use in the benzo(alpha)pyrene hydroxylase assay.

Animals↗
PubMedDate not supplied

Laboratory studies on silica induced toxicity and relationship to carcinogenicity.

A review of published laboratory studies was undertaken to provide insight into the biologic basis for silica induced lung toxicity. Experimental animals exhibit markers of silica induced toxicity similar to those exhibited by humans and may also provide a model for resistant populations. Cell culture studies are useful to discern the roles of specific lung cell types and cell mediators in the development of silica induced fibrotic events. The biochemical relationships between silica induced fibrosis and carcinogenesis have not been fully established. Temporal and dose-response relationships for events linking the two endpoints are unknown. Research in this area will provide a more complete understanding of the relationship between the two disease states and hence of the role of silica exposure in human disease.

Air Pollutants, Occupational↗