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We have measured liver heme oxygenase, a heat shock protein known to be increased under conditions of oxidative stress, to obtain additional evidence for an oxidative stress mechanism in hepatic uroporphyria induced by hexachlorobenzene (HCB). We have studied heme oxygenase at different times during HCB treatment and in two strains of rats (Agus and Wistar strains), which are known to differ in their sensitivity to the porphyria-inducing properties of HCB, in order to ascertain whether the same time course and genetic differences known to exist for the induction of porphyria also apply to hepatic oxidative stress. HCB induced heme oxygenase and accumulation of porphyrins in the liver of rats of both strains; no significant difference was found between the two strains in the HCB-induced heme oxygenase activity. The increased activity of the enzyme was first detected during the early phases of treatment, when a modest increase in liver porphyrins was observed; heme oxygenase remained at induced levels for several weeks during HCB treatment, and was still raised when an increase in total liver iron content and the onset of marked porphyria were also found. In contrast to the effects of HCB, phenobarbitone sodium (given in the drinking water for up to 4 weeks) produced similar elevations of total liver cytochrome P450 as HCB, but did not stimulate heme oxygenase or increase the total liver content of either iron or porphyrins. These results are compatible with an oxidative stress mechanism in HCB-induced liver toxicity and porphyria, but also suggest the existence of successive stages in the induction of hepatic porphyria, with more than one mechanism contributing to the marked accumulation of uroporphyrin.

There are a wide variety of laboratory tests available to assess damage to and functional impairment of the kidneys, although the effectiveness of these tests varies greatly depending upon the site specificity of the damage and to a lesser extent upon the animal species involved. Several traditional tests of renal dysfunction and damage, including plasma creatinine and urea, and urinalysis (dipstick and/or quantitative protein), can be used in the first instance to detect nephrotoxicity. A second tier of specific, targetted indicators (concentration test, urinary enzymes, clearance of analytes, specific proteins, etc.) may then be applied to identify further the site of the lesion and the functional status of the kidneys. The glomerular filtration rate (GFR) may be estimated from the clearance of exogenous and endogenous substances. The difficulty in obtaining accurately timed urine samples limits the value of these tests in small animals, although methods that do not involve urine collection are available. The kidney is the origin of several enzymes found in urine that can be used to monitor the toxic effects of chemicals and therapeutic substances. Selective measurement of enzyme activities in urine can be used to detect the site of the renal lesion after traditional tests have established the presence of renal injury. Separation of proteins in urine by electrophoretic techniques may also be used to discriminate damage to different parts of the nephron. Renal cell excretion in urine is a sensitive but unreliable indicator of acute damage to the proximal tubule. The rate of cell excretion is not a good predictor of the severity of tubular injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Groups of 12 male and 12 female rats were fed diets containing 0 or 8ppm trimethyltin chloride for up to 25 days. All the animals were observed prior to the study start and daily throughout the study for any changes in clinical condition. In addition, detailed clinical observations, including quantitative assessments of landing foot splay, sensory perception, muscle weakness and locomotor activity were monitored during the study. At the end of the study, the rats were killed and subjected to a full Post-mortem. Selected nervous system tissues were removed, processed and examined microscopically. Clinical signs typical of trimethyltin neurotoxicity (e.g. aggression, shaking and convulsions) were seen in rats receiving diets containing 8ppm trimethyltin chloride for as little as 22 days. Neuropathological lesions consisting of extensive neuronal cell necrosis in the limbic region of the brain, vacuolar degeneration of ventral horn cells of the spinal cord and a marginal increase in Wallerian-type degeneration were seen. The study demonstrates that trimethyltin neurotoxicity can be induced by dietary administration and that both male and female rats are equally sensitive.

Acute experimental models of renal damage to the proximal tubular, glomerular, and papillary regions of the rat were produced by administration of hexachloro-1:3-butadiene (HCBD), puromycin aminonucleoside (PAN), and 2-bromoethylamine (BEA), respectively. Several routine indicators of nephrotoxicity, the enzymes alkaline phosphatase and N-acetyl-beta-glucosaminidase, and the molecular weight of protein excretion were determined on urine samples. Tubular damage produced by HCBD or BEA was discriminated both quantitatively and qualitatively from glomerular damage produced by PAN. The latter was characterized by a pronounced increase in protein excretion, especially proteins with molecular weight greater than 40,000 Da. In contrast, protein excretion in tubular damage was raised only slightly and characterized by excretion of proteins of a wide range of molecular weights. Proximal tubular damage caused by HCBD and papillary damage caused by BEA were distinguished both by conventional urinalysis (volume and specific gravity) and by measurement of the two urinary enzymes. Alkaline phosphatase and glucose were markedly and transiently elevated in proximal tubular damage and N-acetyl-beta-glucosaminidase showed a sustained elevation in papillary damage. It is concluded that both selective urinary enzymes and the molecular weight pattern of urinary proteins can be used to provide diagnostic information about the possible site of renal damage.

Summary. Chronic feeding of hexachlorobenzene to rats increases the levels of certain hepatic haemoproteins prior to the onset of hepatic porphyria. The onset of hepatic porphyria is slow and only water soluble porphyrins accumulate in the livers. The accumulation of hexachlorobenzene by the liver is progressive but no direct correlation exists between the amount of HCB in the liver, the extent of hepatic porphyria and the changes in haemoprotein concentration. Similarities between experimental hepatic porphyria induced by hexachlorobenzene and those seen in human symptomatic porphyria are presented and emphasize the usefulness of the hexachlorobenzene model with which to study the human disease.

1. After an intraperitoneal injection of 59Fe the recovery of radioactivity in the liver, but not in other tissues, was increased in cobalt-pretreated rats. There was no proportional increase in the radioactivity recovered from liver haem. 2. Rats were injected intravenously with serum containing protein-bound 59Fe and 125I-labelled albumin as a marker. At various times after injection the specific radioactivities of iron in plasma and of non-haem iron in liver were determined; corrections were applied for the content of plasma in samples of liver. In cobalt-pretreated rats there was a more rapid loss of 59Fe radioactivity from the plasma and a corresponding increase in the uptake of 59Fe into liver non-haem iron. 3. The results are discussed in relation to the possible sites of action of cobalt, and the possibility is considered that only a fraction of the liver non-haem iron may be involved.