Biomedical subjects
Publications and source records attributed to R L Smith.
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Tributyltin in the concentration range 1-4mum failed to stimulate Ca(2+) transport by Lucilia flight-muscle mitochondria in a medium containing KCl and respiratory substrate but devoid of P(i), despite its promotion of a rapid Cl(-)/OH(-) exchange. When 2mm-P(i) was present, concentrations of tributyltin greater than 1mum inhibited the initial rate of Ca(2+) transport and induced efflux of the ion from the mitochondria in Cl(-)- or NO(3) (-)-containing media. Lower concentrations had little effect. Oligomycin added at up to 10mug/mg of mitochondrial protein had no effect on Ca(2+) transport. By contrast, approx. 0.3mum-tributyltin completely inhibited respiration supported by alpha-glycerophosphate in either the presence or absence of added ADP. The data suggest that tributyltin can inhibit Ca(2+) transport in Lucilia flight-muscle mitochondria other than by facilitating a Cl(-)/OH(-) exchange or producing an oligomycin-like effect.
Eight volunteers previously phenotyped for their ability to hydroxylate debrisoquine (four extensive metabolisers (EM), four poor metabolisers (PM) were investigated for their metabolic handling of guanoxan and phenacetin. All three drugs are oxidised at carbon centres. Oxidative dealkylation of phenacetin was determined by measuring the rate of formation of paracetamol. The EM subjects excreted mostly metabolites of guanoxan (mean 29% of dose), whereas the PM group excreted large amounts of unchanged drug (48% of dose). The rate of formation of paracetamol was noticeably slower in the PM group, and, when analysed by minimum estimates of apparent first-order rate constants, the difference between the two phenotypes was significant. Thus the hydroxylation defect shown for debrisoquine metabolism carries over to the oxidative metabolism of phenacetin and guanoxan. Some 5% of the population are genetically defective hydroxylators of drugs. Thus methods for evaluating the metabolism of new drugs in respect of usage and side effects need to be revised.
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1. Ca2+ transport by mitochondria isolated from flight muscle of the sheep blowfly Lucilla cuprina does not occur in the absence of added P1. Maximum rates of transport are attained when about 2.5 mM-phosphate is present. 2. As mitochondria develop, high but not low phosphate concentrations begin to inhibit Ca2+ transport markedly; those isolated from 2-day-old flies for example, are inhibited by about 75% by 20 mM-phosphate. Maximum rates of transport, i.e. those measured in the presence of 2.5 mM-phosphate, begin to decline only when the fly is about 3 days old. 3. Mitochondrial phosphate transport activity does not change during development of the blowfly, but the endogenous concentration of the anion does. At emergence it is about 6nmol/mg of protein, increases to about 17 nmol/mg of protein at 2-3h and then rapidly declines to reach less than 5 nmol/mg of protein after 2 days of adult life. 4. Studies on the effect of phosphate on oxidation of alpha-glycerophosphate in the absence and presence of ADP reveal a lack of inhibition by high phosphate concentrations indicating that the anion does not influence Ca2+ transport by preventing the generation of the proton electrochemical gradient across the inner membrane. 5. It is concluded that the molecular assembly in the inner membrane of Lucilla mitochondria responsible for transporting Ca2+ is fully developed at emergence and remains so for at least 2-3 days of adult life. The possibility exists that Ca2+-transport activity in these mitochondria is controlled at least in part by P1.
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A 25 year old black woman who had manifestations of Gaucher's disease since one year of age is described. This patient had clinically significant cardiac, renal and pulmonary involvement with Gaucher's disease. Interstitial infiltration of the myocardium by Gaucher cells caused decreased left ventricular compliance and decreased cardiac output. In the kidney, Gaucher cells were present in the mesangium of the glomeruli and the interstitium of the cortex. Also, electron dense, intramembranous granular deposits were seen in glomeruli on electron microscopy. The pulmonary findings included pulmonary arterial hypertension, accentuated basilar deposition of glucocerebroside in the interstitium of alveolar septums and fatal bone marrow embolization.
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A case of premature ageing (progeria) in a 3-year-old Indian child is described. The conjugations of paracetamol with glucuronic acid and sulphate, of benzoic acid with glycine and of phenylacetic acid with glutamine have been investigated in this child, in view of suggestions that these reactions are impaired in old age. The results suggest that the glucuronic acid conjugation pathway may be quantitatively less important in the progeric child than in normal children and adults.
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