Pulmonary biochemical assessment of fenitrothion toxicity in rats.
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Biomedical subjects
Publications and source records attributed to M F Khan.
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In a working class industrial area of Karachi hundred consecutive Pathans presenting to a family physician with potency disorder were examined. After exclusion of those with structural or drug related conditions, a structured proforma was introduced. Their presentation, associated symptoms and background pointed to masked depression and lack of sex education. Symptoms of anxiety were noticed in 49% and depressive features in 43%. The guilt feelings were reinforced by Hakims and lay literature which stress more on masturbation (79%) and spermatorrhoea (60%) and not extra-marital intercourse (52%) or bestiality (39%).
The effect of intratracheally instilled slate dust on the phospholipid profile, and 14C-acetate incorporation into the lipids of lung lavage, whole lung tissue and its subcellular fractions, has been studied in rats. The acellular fraction of lung lavage showed a decrease in the phospholipid content at 4 days and then an increase at 40 days of dust exposure, whereas the cellular fraction showed the reverse. The order of 14C-acetate incorporation into total lipids and individual phospholipids showed a parallel trend. The rate of incorporation with total lipids of lung tissue was higher at the two stages of dust exposure and a similar pattern prevailed in the subcellular fractions, i.e. mitochondrial, microsomal and cytosolic fraction. Acetate incorporation was highest in mitochondria, followed by the microsomes. An increase in the microsomal and mitochondrial cholesterol levels was also observed. There was no significant change in the solvent-extracted 14C-counts of whole plasma, trichloroacetic acid (TCA) precipitate and TCA supernatant of plasma. The results indicate that slate dust causes an enhanced synthesis of pulmonary surfactant and other lung lipids and, therefore, has an effect on the metabolism of type II alveolar epithelial cells.
Recently we reported elimination of radioactivity from [14C]heptachlor from body stores of lactating ovines, mainly into excreta rather than milk, contrasting sharply with bovines. To further assess heptachlor metabolism and clearance by ovines, 12 fine-wool wether lambs (41 +/- 3 kg) housed in metabolism stalls were fed pelleted alfalfa hay (96%) plus molasses (3%) ad libitum and were dosed i.p. once with [14C]heptachlor (1.643 mg/kg body wt; sp. act. = .89 microCi/mg). Feces and urine were collected separately and quantitatively. Light mineral oil was mixed with feed (5 g/100 g) of six lambs and trans-stilbene oxide, an inducer of biotransformational enzymes, was administered i.p. (4 g/hd initially; 2 g/hd daily thereafter) through 20 d to three lambs given each mineral oil treatment, in 2 x 2 factorial arrangement. Feces, urine, blood, bile and body tissues were assayed for total 14C activity. Radioactivity (heptachlor and [or] metabolites) eliminated into excreta during 21 d amounted to 34 to 36% of dose administered, of which 67% appeared in urine and 33% in feces. Biological half-time for elimination into excreta was 11.3 d [Kel = -.061/d], similar to 11.7 d we reported for lactating ewes. Clearance from blood had T1/2 = 14 d. Neither mineral oil nor trans-stilbene oxide altered rate or route of 14C activity excreted or concentrations of 14C activity in blood. Results confirmed that ovines eliminate heptachlor much more rapidly than bovines.
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Elimination of [14C]heptachlor from body burdens of sheep was measured using mature ewes nursing single offspring, and the influence of exogenous ovine growth hormone (oGH) on elimination was studied. Six ewes (62 +/- 2.5 kg BW) were dosed (i.p.) once with [14C]heptachlor (2.04 mg/kg Bw; .88 microCi/mg heptachlor) and three were treated additionally with oGH (oGH; 5 mg/d) for 21 d. Three additional ewes served as controls. Excreta were collected each day for 21 d. Milk and blood were collected every 3rd d until ewes were euthanized at d 21. 14C activity was measured in excreta, milk, blood and tissues. Total cumulative activity of [14C]heptachlor and(or) metabolites in excreta (21 d) did not differ (P greater than .20) in ewes given oGH (25 +/- 2%) vs none (23 +/- 2%). Milk yield and protein content were unaffected (P greater than .10) by oGH. Ewes given oGH eliminated 2.2 +/- 2% of total 14C dosage into milk during 21 d, whereas ewes untreated with oGH eliminated 1.3 +/- .2% (P less than .10); total 14C activity eliminated into milk plus excreta was similar for ewes given oGH or none (P greater than .10). For all six ewes, half-times (T1/2) for distribution and elimination of 14C activity (heptachlor and metabolites) were 1.5 d and 11.7 d, respectively. Blood concentrations of 14C activity during 21 d yielded elimination half-time as 23 d. Unlike bovines, which eliminate heptachlor slowly (T1/2 approximately 70 to 80 d) and mainly into milk fat, lactating ovines eliminated heptachlor and(or) metabolites mainly into excreta and about sixfold faster than bovines.
Intracellular thiols (LSH), superoxide dismutase (SOD) and plasma thiols (PSH) are thought to have an important role in the protection of tissues from damage by oxygen-derived free radicals. The change in the levels of activity of these substances in patients with active rheumatoid arthritis treated with sulphasalazine for 6 months was assessed in 22 patients. Over this time there was a marked improvement in disease activity. This was accompanied by an early increase in red cell LSH and decrease in SOD, although by 6 months these changes had completely reversed. In addition the negative correlation between these indices at week 0 had disappeared by week 6. Over the 6 months there was a steady rise in PSH. The change in PSH is slow and is thus more likely to reflect a change in the disease process rather than an active role for the thiol, but the early changes in intracellular parameters may be of importance in the action of this drug. These changes are similar to changes found with other second-line drugs. It is also of interest that a drug which does not itself possess a thiol group is capable of altering the thiol status of cells.
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Silicic acid has been shown to be the main pathogenic factor in the toxicity of silicate dusts. Our earlier findings have shown the interaction of silica (silicic acid) with rat plasma and lung proteins in vitro. In the present communication, we report the binding of silica with plasma protein in vivo. The significance of in vivo silica-protein interaction is discussed in relation to its toxicity and clearance from the body.
Genetic distances have been estimated among three Muslim groups, the Sunni, Shia and the Bohra, and a Hindu group, the Brahman, from five districts of the centrally located state of Madhya Pradesh in India. The distances are based on five genetic systems, the ABO, MN and Rh blood groups. PIC taste sensitivity and colour blindness. None of the 6 distances among the 4 groups was statistically significant. However, cluster analysis showed that Sunni and Shia form a very close cluster which is successively joined by Brahman and Bohra, the latter having comparatively large distances from all the other groups.
Morpho-behavioural distances between three endogamous Muslim groups (Sunni, Shia and Bohra) and one Hindu group (Brahman) of Madhya Pradesh, separately for males and females, were estimated. All the differences were statistically significant. The male and female distances were combined into a pooled distance. The Bohra group was found to be distant from all the other groups in both males and females. The relationships between the other three were different in the two sexes-Sunni and Shia forming the closest cluster in males and Sunni and Brahman in females. The Sunni were intermediate between the Shia and the Brahman in both sexes. The morpho-behavioural distances were compared with the genetic distances.
The biochemical changes in rat lungs due to intratracheal instillation of 50 mg of slate dust have been studied up to 150 days of dust exposure. The remarkable feature of lung changes was the turnover of collagen in experimental animals after 90 days, reaching substantially higher values at 150 days. A concurrent increase in hexosamine and sialic acid contents was also observed. The phospholipid content in the whole lung tissue, as well as in the mitochondria, was generally higher in the dust-treated rats, particularly at the later stages. The mitochondrial cytochrome c oxidase and glutamate dehydrogenase activities increased, whereas monoamine oxidase was marginally affected. Mitochondria from experimental animals appeared to be in a swollen state, particularly at 120 days of exposure. The above results suggest that slate dust exerts its toxic effects by causing alterations in the tissue make-up as well as in the mitochondrial functioning of the lung.
Composition of the erythrocyte ghost membrane obtained from slate-dust-lysed and hypotonically lysed erythrocytes were compared in vitro. The protein and cholesterol contents were unaltered, whilst phospholipid and glycosamine contents decreased significantly in the slate-dust-lysed preparation of erythrocyte ghost membrane. Na+, K+-ATPase activity remained unchanged, whilst acetylcholinesterase activity was decreased slightly by slate dust treatment. Further, binding of silicic acid, dissolving out of slate dust, was observed with a component of erythrocyte ghost membrane protein having molecular weight around 90 000 daltons. The significance of the findings is discussed.
Silica dissolving out from the slate dust was found to bind with plasma protein and purified bovine serum albumin. At 24 h of incubation at 37 degrees C binding affinity of silica (microgram of silica bound/mg of protein) with plasma protein and bovine serum albumin was found to be 0.59 and 0.44, respectively. By molecular exclusion chromatography using Sephadex G-200, silica binding protein of plasma was determined to be of mol. wt. around 67000. Similar proteins having silica binding capacity (mol. wt. 70000 and 85000) were also found in rat lung but these proteins unlike their plasma counterpart were glycoprotein in nature. Polyacrylamide gel electrophoresis of plasma and protein rich lung fraction show that proteins upon binding with silica undergo mobility changes. Significance of the existence of silica binding protein in plasma and lung of rat in relation to silica toxicity is discussed.
As part of a detailed experimental study of the pathogenicity of disease of slate dust workers, the early biochemical changes in rat lung from 1 to 90 days after intratracheal inoculation of slate dust of particle size below 5 micron were investigated. A severalfold increase in free cell population (initially macrophages) was elicited by the dust. The free activity of acid phosphatase tended to increase along with a break of lysosomal latency with increasing exposure period. However, actual release of enzyme activity into the acellular fraction was low. The phospholipid content varied both in cellular and acellular fractions, indicating altered turnover of membrane lipids and surfactants. At advanced periods of the study, sialic was found to be released into the acellular fraction, indicating membrane damage. Considerable decrease in glucose-6-phosphate dehydrogenase activity and free sulfhydryl content and enhanced osmotic fragility of erythrocytes were also recorded. These results indicate the potential toxicity of slate mine dust.
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