Biomedical subjects
Publications and source records attributed to M G Cox.
An algorithm is described for the calibration of immunoassay curves. It employs a quadratic spline as the approximating function. The number and positions of the knots of the spline are chosen adaptively. The behaviour of the spline is controlled so that it preserves the key properties of the underlying function.
2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of [14C]TMP (4.4 mmol/kg; 2 microCi/mmol). Radiolabeled material in kidney, liver, and plasma was determined at 4, 8, 12, 24, and 48 hr after dosing. Maximum concentration of TMP-derived radioactivity in kidney, liver, and plasma of male rats was found after 12 hr (1252, 1000, and 403 nmol eq/g, respectively), whereas those measured in females were found after 8 hr (577, 1163, and 317 nmol eq/g, respectively). A selective retention of the TMP-derived radiolabel in the kidneys of male rats was noted when peak tissue concentration was expressed as a percentage of administered dose. Kidney concentrations of TMP-derived radiolabel increased in a nonlinear, but dose-dependent, manner; the kidney to plasma ratio was greater at low doses than at higher doses. Increased retention of radiolabel material in the kidney was associated with a significant increase in renal concentration of the male-rat-specific protein, alpha 2u-globulin, 24 and 48 hr after TMP administration. Total radioactivity collected in urine 48 hr after TMP administration was similar in males and females (32 and 31% of dose). Identification and quantitation of the urinary metabolites of TMP showed that both male and female rats metabolize TMP via the same pathway and at a similar rate. Female rats, however, excreted more conjugates of 2,4,4-trimethyl-2-pentanol in urine than males. 2,4,4-Trimethyl-2-pentanol was the major metabolite present in the male rat kidney, but was absent in the female rat kidney. The renal retention of 2,4,4-trimethyl-2-pentanol appears to account for the delayed clearance observed in the disposition of [14C]TMP-derived radiolabel. Based on the concomitant accumulations in renal alpha 2u-globulin concentration and renal 2,4,4-trimethyl-2-pentanol concentration, an association is speculated between these two components. The male-rat-specific accumulation of 2,4,4-trimethyl-2-pentanol may therefore reflect the accumulation of a "metabolite-alpha 2u-globulin" complex. This may be relevant to the male-rat-specific nephrotoxicity produced by TMP.
The pathologic significance of intracytoplasmic protein droplet accumulation within renal tubular epithelial cells induced experimentally in male rats after exposure to various environmental chemicals, such as unleaded gasoline (UG), is poorly understood. 2,2,4-Trimethylpentane (TMP), a component of UG, also is a potent inducer of protein droplets in male rats. This study documents a strong correlation between protein droplet accumulation, single cell necrosis, and regeneration of the male F344 rat nephron during a 3-week exposure regimen to a wide dose range of inhaled UG or gavaged TMP covering several orders of magnitude (2 to 2000 ppm of UG and 0.2 to 50 mg/kg of TMP, respectively). Autoradiographic analyses of various segments of the nephron were conducted after continuous administration of [methyl-3H]thymidine via osmotic pumps implanted during the last week of UG or TMP exposure. The P2 segment of the proximal tubule of control rats from both experiments had a higher rate of cell turnover (approximately 11%) than the adjacent P1 (approximately 2%) or P3 segments (approximately 3%). The P2 segment of rats exposed to UG or TMP responded with additional dose-related (up to 6-fold) increases in cell turnover. The extent and localization of cell proliferation closely paralleled the extent and severity of accumulation of crystalloid protein droplets and single cell necrosis. Biochemical and immunohistochemical studies have shown that protein droplets in male, but not female rats, consist primarily of alpha-2u-globulin, a low molecular weight protein synthesized by the liver under androgenic control. Increased cell turnover in the P2 segment of male rats may be related to altered catabolism of alpha-2u-globulin. This accelerated cell proliferation may be an essential factor in the development of renal cancer in male rats exposed to UG or other volatile hydrocarbons.
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We have synthesized N2-[4-(2,2,6,6-tetramethyl-1-piperidinyloxy)]actinomycin D And the related 1,2-diaminoethane and 1,3-diaminopropane derivatives and evaluated their biological properties. Binding studies with the spin-labeled actinomycin D analogues and DNA were carried out by using circular dichroism, electron spin resonance, and thermal denaturation. These studies have suggested that the derivatives bind to DNA and that their DNA-binding modes are similar but not identical. Spin-labeled actinomycin D derivatives were less potent in inhibiting Escherichia coli DNA-dependent RNA polymerase reaction than actinomycin D and were less toxic to L1210 cells in vitro than the parent compound. Spin-labeled actinomycin D derivatives were more common than the parent compounds against P-388 leukemia cells in vitro with little or no toxicity.