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ABSTRACT: Urinary porphyrin excretion rates were evaluated in male rats of the Sprague-Dawley, Fischer 344, and Osborne-Mendel strains, and in female Fischer 344 rats, in order to identify an appropriate rat model for long-term studies of chemical-induced porphyria. Sprague-Dawley rats displayed a wide interanimal range in total 24-hr porphyrin excretion rates, from 0.9 to 59.6 nmol/24 hr (64-fold). Additionally, individual Sprague-Dawley rats varied by up to 5-fold in total porphyrins excreted from week to week over a 4-week period. Osborne-Mendel rats displayed a 12-fold interanimal difference in 24-hr total porphyrin excretion rates (ranging from 6.2 to 71.1 nmol/24 hr) and up to 4-fold individual variation from 1 week to another. In contrast, rats of the Fischer 344 strain displayed no significant differences in porphyrin excretion rates either among different animals or for individuals from week to week. Determination of individual porphyrin concentrations in the urine demonstrated that inconsistencies in total porphyrin concentration were attributable principally to differences in coproporphyrin concentrations. Frequency analysis of 24-hr coproporphyrin excretion levels among Sprague-Dawley rats demonstrated a widespread range encompassing low levels comparable to those of Fischer rats, high levels similar to those of most Osborne-Mendel rats, as well as intermediate levels. The mean total porphyrin excretion rate among female Fischer 344 rats was 1.2 +/- 0.51 nmol/24 hr, compared to 2.1 +/- 0.50 nmol/24 hr among male Fischer rats. Maturation and aging were found to have little influence on porphyrin excretion rates in male Fischer 344 rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Fundamental and Applied Toxicology 12/1992; 19(4):538-44.
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ABSTRACT: Measurement of urinary porphyrin excretion patterns (porphyrin profiles) is useful in the diagnosis and evaluation of diseases and disorders of porphyrin metabolism. However, experimental investigation of such disorders with rodent models has been hampered by the lack of an efficient procedure for the isolation and quantitative evaluation of porphyrins in rodent urine. This article describes an analytic procedure that overcomes the principal difficulties encountered with determination of porphyrins in rodent urine, including the loss of porphyrins during their isolation and interference of porphyrin fluorescence by contaminating materials. The procedure entails application of an acidified urine sample to a preconditioned C-18 preparatory column, preferential separation of essentially all potentially interfering contaminants by sequential phosphate-methanol elution, and selective isolation of porphyrins, which are then separated and quantitated by high-performance liquid chromatography and spectrofluorometric techniques. This method has been used to characterize urinary porphyrin excretion patterns in male rats and to define the distinctive changes in porphyrin profiles associated with prolonged exposure to porphyrinogenic metals. The porphyrin excretion patterns of male and female human subjects are also described. This method is applicable to the investigation of urinary porphyrin profile changes associated with exposure to a wide range of porphyrinogenic chemicals in both animals and human subjects.
Journal of Laboratory and Clinical Medicine 09/1992; 120(2):272-81. · 2.62 Impact Factor
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ABSTRACT: Glutathione (GSH), a major cellular antioxidant, is elevated 2- to 3-fold in kidneys of rats during prolonged treatment with mercury as methyl mercury hydroxide (MMH). Increased renal GSH is accompanied by a dose- and time-related elevation in the relative abundance of mRNA hybridizable to a cDNA probe which encodes renal gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis. Renal GCS mRNA is maximally elevated 4.4-fold at 3 weeks following initiation of MMH treatment. Enhancement of GSH and GCS mRNA content corresponds to a relative sparing of renal cells from oxidative tissue damage during MMH exposure. These observations suggest that increased synthesis of GSH at the genetic level occurs as an initial adaptive response to mercury-induced oxidative stress in kidney cells.
Archives of Biochemistry and Biophysics 08/1992; 296(1):350-3. · 2.93 Impact Factor
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ABSTRACT: Studies were conducted to define the specific changes in the urinary porphyrin excretion pattern (porphyrin profile) and the time course of those changes in rats exposed to mercury as methyl mercury hydroxide (MMH) at 5 or 10 ppm in the drinking water for up to 30 weeks. The urinary porphyrin profile elicited by MMH is uniquely characterized by highly elevated levels of 4- and 5-carboxyl porphyrins, and of a third atypical porphyrin with as yet undetermined chemical characteristics. Changes in the porphyrin profile were observed as early as 1 or 2 weeks following initiation of exposure to MMH at 10 or 5 ppm, respectively, and were sustained as long as 40 weeks following cessation of MMH treatment. The magnitude of the urinary porphyrin profile at either MMH dose level increased progressively during the course of mercury treatment and was highly correlated with the renal mercury concentration. A subsequent decline in the magnitude of the urinary porphyrin profile in animals exposed to 10 ppm MMH for more than 10 weeks was associated with the accumulation of high levels of Hg2+ in kidney cells and loss of renal functional status. These findings demonstrate that mercury elicits a unique change in the urinary porphyrin excretion pattern which is related to the dose and duration of mercury treatment. The association of urinary porphyrin excretion rates with renal mercury content and functional status suggests that urinary porphyrin profiles may serve as a useful biomarker of mercury accumulation and nephrotoxicity during prolonged mercury exposure.
Toxicology and Applied Pharmacology 10/1991; 110(3):464-76. · 4.45 Impact Factor
