Effectiveness of (PhSe)2 in protect against the HgCl2 toxicity

This work investigated the preventive effect of diphenyl diselenide [(PhSe)₂] on renal and hepatic toxicity biomarkers and oxidative parameters in adult mice exposed to mercury chloride (HgCl₂). Selenium (Se) and mercury (Hg) determination was also carried out. Mice received a daily oral dose of (PhSe)₂ (5.0 mg/kg/day) or canola oil for five consecutive days. During the following five days, the animals were treated with a daily subcutaneous dose of HgCl₂ (5.0 mg/kg/day) or saline (0.9%). Twenty-four hours after the last HgCl₂ administration, the animals were sacrificed and biological material was obtained. Concerning toxicity biomarkers, Hg exposure inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), serum alanine aminotransferase (ALT) activity and also increased serum creatinine levels. (PhSe)₂ partially prevented blood δ-ALA-D inhibition and totally prevented the serum creatinine increase. Regarding the oxidative parameters, Hg decreased kidney TBARS levels and increased kidney non-protein thiol levels, while (PhSe)₂ pre-treatment partially protected the kidney thiol levels increase. Animals exposed to HgCl₂ presented Hg content accumulation in blood, kidney and liver. The (PhSe)₂ pre-treatment increased Hg accumulation in kidney and decreased in blood. These results show that (PhSe)₂ can be efficient in protecting against these toxic effects presented by this Hg exposure model.     

Zinc and N-acetylcysteine modify mercury distribution and promote increase in hepatic metallothionein levels

This study investigated the ability of zinc (Zn) and N-acetylcysteine (NAC) in preventing the biochemical alterations caused by mercury (Hg) and the retention of this metal in different organs. Adult female rats received ZnCl₂ (27 mg/kg) and/or NAC (5 mg/kg) or saline (0.9%) subcutaneously and after 24 h they received HgCl₂ (5 mg/kg) or saline (0.9%). Twenty-four hours after, they were sacrificed and analyses were performed. Hg inhibited hepatic, renal, and blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, decreased renal total thiol levels, as well as increased serum creatinine and urea levels and aspartate aminotransferase activity. HgCl₂-exposed groups presented an important retention of Hg in all the tissues analyzed. All pre-treatments demonstrated tendency in preventing hepatic δ-ALA-D inhibition, whereas only ZnCl₂ showed this effect on blood enzyme. Moreover, the combination of these compounds completely prevented liver and blood Hg retention. The exposure to Zn and Hg increased hepatic metallothionein levels. These results show that Zn and NAC presented promising effects against the toxicity caused by HgCl₂.     

Photodynamic and light independent action of 8 to 2 carboxylic free porphyrins on some haem-enzymes

Backgrounds and aims: skin lesions in cutaneous porphyrias appear to be determined by the structural properties of the porphyrins accumulated. To better understand the relationship between the structure and physicochemical properties of porphyrins and their specific effect on protein configuration, the action of a whole range of 8 to 2 carboxylic porphyrins has been studied. Materials and methods: δ-aminolevulinic acid dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D) partially purified from bovine liver, were exposed to 10 μM uroporphyrin (Uro), phyriaporphyrin (Phyria), hexaporphyrin (Hexa), pentaporphyrin (Penta), coproporphyrin (Copro) or protoporphyrin (Proto), either in the dark or under UV light. All experiments were performed in the enzyme solutions after removing the porphyrins. Results: under both illuminating conditions, all porphyrins inactivated the enzymes (20–70% under control values), indicating photodynamic action mediated by oxidative reactions and conformational changes due to direct binding of porphyrins to the protein. Total thiol content in ALA-D was not significantly changed by most porphyrins under UV light, while all porphyrins increase total sulfhydryl groups in PBG-D (23–52% over the control values) indicating changes in the redox status of SH residues. Free amino groups were reduced by all porphyrins in ALA-D (23–56% under controls), instead they were enhanced in PBG-D (23–51% over controls), suggesting protein fragmentation. The formation of molecular aggregates would be the consequence of cross-links between oxidation products, while fragmentation can be attributed to either rupture of disulphur bridges and/or enhancement of free amino groups on the protein enzyme. Conclusions: the effect of the porphyrins on enzyme activity, total SH groups and free amino groups content, was different for ALA-D and PBG-D, even under the same illuminating conditions. On the basis of these results, no correlation between enzyme alterations and the physico-chemical properties of porphyrins could be established.     

Effects of HgCl2 on porphobilinogen-synthase (E.C. 4.2.1.24) activity and on mercury levels in rats exposed during different precocious periods of postnatal life

Porphobilinogen-synthase (PBG-synthase) is an enzyme extensively used as a bioindicator of metals and other oxidizing agents. The objective of this study was to verify the effects of HgCl(2) (5mg/kg/day, s.c.), a metal that mainly affects the nervous and renal systems, on kidney, liver and brain from rats exposed during one of the phases considered critical for development. Mercury decreased PBG-synthase activity from liver, kidney and brain and altered corporal, renal and cerebral weights. The kidney was the most sensitive tissue. It accumulated a large amount of metal and PBG-synthase activity was decreased up to 50%. The second period seemed to be the most sensitive, because in this phase the rats presented alterations in body, brain and kidney weights, and there was also an expressive inhibition in hepatic and renal PBG-synthase activities. In general, large quantities of metal accumulated in the tissues are in agreement with the inhibition verified in these tissues.     

Lactating and nonlactating rats differ to renal toxicity induced by mercuric chloride: the preventive effect of zinc chloride

This study evaluated the effects of HgCl₂ on renal parameters in nonlactating and lactating rats and their pups, as well as the preventive role of ZnCl₂. Rats received 27 mg kg^?1 ZnCl₂ for five consecutive days and 5 mg kg^?1 HgCl₂ for five subsequent days (s.c.). A decrease in δ‐aminolevulinic acid dehydratase (δ‐ALA‐D) activity in the blood and an increase in urine protein content in renal weight as well as in blood and urine Hg levels were observed in lactating and nonlactating rats from Sal―Hg and Zn―Hg groups. ZnCl₂ prevented partially the δ‐ALA‐D inhibition and the proteinuria in nonlactating rats. Renal Hg levels were increased in all HgCl₂ groups, and the ZnCl₂ exposure potentiated this effect in lactating rats. Nonlactating rats exposed to HgCl₂ exhibited an increase in plasma urea and creatinine levels, δ‐ALA‐D activity inhibition and histopathological alterations (necrosis, atrophic tubules and collagen deposition) in the kidneys. ZnCl₂ exposure prevented the biochemical alterations. Hg‐exposed pups showed lower body and renal weight and an increase in the renal Hg levels. In conclusion, mercury‐induced nephrotoxicity differs considerably between lactating and nonlactating rats. Moreover, prior exposure with ZnCl₂ may provide protection to individuals who get exposed to mercury occupationally or accidentally. Copyright © 2014 John Wiley & Sons, Ltd.     

Peptidic models for the binding of Pb(II), Bi(III) and Cd(II) to mononuclear thiolate binding sites

Herein, we evaluate the binding of Pb(II) and Bi(III) to cysteine-substituted versions of the TRI peptides [AcG-(LKALEEK)₄G-NH₂] which have previously been shown to bind Hg(II) and Cd(II) in unusual geometries as compared with small-molecule thiol ligands in aqueous solutions. Studies of Pb(II) and Bi(III) with the peptides give rise to complexes consistent with the metal ions bound to three sulfur atoms with M–S distances of 2.63 and 2.54 Å, respectively. Competition experiments between the metal ions Pb(II), Cd(II), Hg(II) and Bi(III) for the peptides show that Hg(II) has the highest affinity, owing to the initial formation of the extremely strong HgS₂ bond. Cd(II) and Pb(II) have comparable binding affinities at pH > 8, while Bi(III) displays the weakest affinity, following the model, M(II) + (TRI LXC)₃ ^3? → M(II)(TRI LXC)₃ ^?. While the relevant equilibria for Hg(II) binding to the TRI peptides corresponds to a strong first step forming Hg(TRI LXC)₂(HTRI LXC), followed by a single deprotonation to give Hg(TRI LXC)₃ ^?, the binding of Cd(II) and Pb(II) is consistent with initial formation of M(II)(TRI LXC)(HTRI LXC)₂ ⁺ at pH < 5 followed by a two-proton dissociation step (pK _a2) yielding M(II)(TRI LXC)₃ ^?. Pb(II)(TRI LXC)(HTRI LXC)₂ ⁺ converts to Pb(II)(TRI LXC)₃ ^? at slightly lower pH values than the corresponding Cd(II)–peptide complexes. In addition, Pb(II) displays a lower pK _a of binding to the “d”-substituted peptide, (TRI L12C, pK _a2 = 12.0) compared with the “a”-substituted peptide, (TRI L16C, pK _a2 = 12.6), the reverse of the order seen for Hg(II) and Cd(II). Pb(II) also showed a stronger binding affinity for TRI L12C (K _bind = 3.2 × 10⁷ M^?1) compared with that with TRI L16C (K _bind = 1.2 × 10⁷ M^?1) at pH > 8.     

Protective effect of quercetin on some hematological parameters in rats exposed to cadmium

ABSTRACT

We investigated the effects of quercetin (Q) on some hematological parameters and determined the percentage of alpha-naphthyl acetate esterase (ANAE) positive lymphocytes in rats that had been exposed to cadmium (Cd). Thirty male Wistar albino rats were divided into four groups: control (C), quercetin (Q), cadmium (Cd) and Q + Cd (CdQ). Blood samples were taken to assess erythrocytes (RBC), leukocytes (WBC), hemoglobin levels (Hb), hematocrit values (Hct), platelets (PLT), alpha-naphthyl acetate esterase (ANAE) positive lymphocytes. RBC, Hb, Hct; the number of PLT significantly decreased in the Cd group. To the contrary, these parameters were increased significantly in the CdQ group compared to the Cd group. Although we found a significant increase in total WBC count and neutrophil percentage, the number of lymphocytes decreased in the Cd group compared to the other three groups. Also, the percentage of peripheral blood ANAE positive lymphocytes decreased significantly in the Cd group (p < 0.05). Q exhibits positive effects on some hematological characteristics and the percentage of ANAE positive lymphocyte in cases of acute CD toxicity.     

Metallothionein, zinc, and mercury levels in tissues of young rats exposed to zinc and subsequently to mercury

Several studies have described mercury toxicity and the role of metallothioneins (MT) in the detoxification and regulation of metal homeostasis. However, little data exist on this topic during the specific post-natal developmental phase in young mammals. This developmental phase is particularly important since young animals are more sensitive to toxicants than adults. The objective of this work was to investigate whether MT participates in the mechanism of protection conferred by zinc pre-treatment on the toxic effects induced by mercury in neonate rats. Pups were exposed to ZnCl(2) (5 doses of 27 mg/kg/day, s.c.) and subsequently to HgCl(2) (5 doses of 5 mg/kg/day, s.c.); metal (Zn and Hg) and MT contents were analyzed in the liver, kidney, and blood. MT was induced in the liver and kidney of pups of both Zn-sal and Zn-Hg groups, although the greatest increase was in neonates exposed to Zn only. A direct relationship exists between MT and metals for both hepatic and renal tissues, which indicates that the increase in metal levels occurs in parallel to the increase in MT content. Although the heat-treated cytosolic fraction is rich in MT and metals, higher Zn and Hg contents were detected in the insoluble fraction of all tissues. These results suggest that MT is, at least in part, responsible for preventing Hg accumulation in the liver and blood and decreasing renal toxicity.     

Protective effect of zinc supplementation on blood antioxidant defense system in rats exposed to cadmium

The aim of this study was to assess the effects of subchronic exposure to cadmium (Cd) on the antioxidant defense system of red blood cells (RBCs) and lipid peroxide concentration in the plasma, as well as the possible protective role of zinc (Zn). For this purpose, 60 male Wistar rats (8 weeks old) were divided into three groups: the first group was exposed to Cd in the form of CdCl₂, administered in five doses (each of 0.4 mg Cd/kg BW) on days 5, 10, 15, 20 and 25, giving a total dose of 2 mg Cd/kg BW, i.p.; the second group was simultaneously exposed to Zn and Cd with the same timeline and the same doses of Cd as the first group but with, in addition, injections of Zn in the form of ZnCl₂, administered in doses of 0.8 mg Zn/kg BW, giving a total dose of 4 mg Zn/kg BW, i.p.; a control group received 0.5 mL of physiological saline in an identical manner.

It was shown that exposure to Cd induced a significant decrease (p<0.05) in superoxide dismutase (Zn/Cu SOD) and catalase (CAT) activities in RBCs. Increased lipid peroxide concentration, measured by thiobarbituric acid reactive substances (TBARS), was also observed in the plasma of cadmium-exposed rats. Cd had no effect on glutathione peroxidase (GSH-Px) activity. Zn administration had a beneficial effect on the Cd-induced decrease in Zn/Cu SOD activity (p<0.05) but not on CAT activity. Animals receiving Cd and Zn simultaneously had significantly (p<0.05) lower concentrations of lipid peroxides than rats exposed to Cd alone. Our results indicate that Cd causes oxidative stress and that Zn supply in conditions of exposure to Cd can partially protect against Cd-induced oxidative stress.     

Protective effect of omega-3 fatty acid against mercury chloride intoxication in mice

The aim of this study was to investigate the protective effect of omega-3 fatty acid in HgCI₂ toxicity in mice. Levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) and total sialic acid (TSA), and histopathological changes in selected organs were evaluated. Twenty-eight mice were equally divided into 4 groups, namely Groups I–IV. Group I animals received intraperitoneal (ip) injection of physiological saline solution; Group II animals received ip injection of 0.4 mg/kg/day HgCI₂; Group III animals received ip injection of 0.4 mg/kg/day HgCI₂ in addition to subcutaneous (sc) injection of 0.5 g/kg/day omega-3 fatty acid; and Group IV animals received sc injection of 0.5 g/kg/day omega-3 fatty acid. All treatments lasted 7 days. The levels of MDA, NO and TSA were significantly higher in Group II and lower in Groups III and IV as compared to the Group I. GSH level was the highest in Group IV. In histopathology, severe degeneration in liver and kidney was observed in Group II animals. These degrading changes were seen to be reduced greatly in Group III animals. The results suggested that omega-3 fatty acid might attenuate HgCI₂-induced toxicity by improving antioxidant status and acute phase response in mice.     

Daily zinc supplementation effect on zinc deficiency in rats during prolonged restriction of motor activity

The objective of this investigation was to evaluate the effect of 47 mg zinc supplementation on deficiency of zinc in rats during 98 d of restriction of motor activity (hypokinesia), which appeared by higher plasma zinc concentration. One Hundred 13-week-old Sprague-Dawley male rats weighing 360–390 g were used to perform the studies: They were equally divided into four groups: 1. Unsupplemented control animals (UCA); 2. Unsupplemented hypokinetic animals (UHA); 3. Supplemented control animals (SCA); and 4. Supplemented hypokinetic animals (SHA). For the simulation of the effect of hypokinesia (HK), the UHA and SHA were kept in small individual cages made of wood, which restricted their movements in all directions without hindering food and water intake. The SCA and SHA received daily with their food an additional amount of zinc. Before and during the experimental period of 98 d, plasma, urinary and fecal zinc, balance of zinc, food intake, and body weight were determined at different intervals. In the SHA and UHA, the concentration of zinc in plasma, and the elimination of zinc in urine and feces increased significantly when compared with the SCA and UCA, whereas the balance of zinc was negative. The body weight and food intake decreased significantly in the SHA and UHA when compared with the SCA and UCA. The increased plasma concentration of zinc in both the SHA and UHA groups was in contrast to the observed hypozincnemia during prolonged immobilization as during prolonged hospitalization. This reaction suggests that there may be some other mechanisms that are affecting the process of control and regulation of zinc metabolism during prolonged HK. It was concluded that exposure to prolonged restriction of motor activity of rats induces significant increases in plasma concentration, fecal and urinary elimination of zinc in the presence of negative zinc balance and regardless the daily intake of large amounts of zinc with their food, leading to zinc deficiency.     

Aluminum-induced oxidative stress in rat brain: response to combined administration of citric acid and HEDTA

Aluminum, a known neurotoxic substance, has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. Therapeutic efficacy of combined administration of citric acid (CA) and N-(2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) was evaluated in decreasing blood and brain aluminum concentration and parameters indicative of hematological disorders and brain oxidative stress. Adult male wistar rats were exposed to drinking water containing 0.2% aluminum nitrate for 8 months and treated once daily for 5 consecutive days with CA (50 mg/kg, orally) or HEDTA (50 mg/kg, intraperitoneally) either individually or in combination. Aluminum exposure significantly inhibited blood delta-aminolevulinic acid dehydratase while increased zinc protoporphyrin confirming changed heme biosynthesis. Significant decrease in the level of glutathione S-transferase in various brain regions and an increase in whole brain thiobarbituric acid reactive substance, and oxidized glutathione (GSSG) levels were also observed. Glutathione peroxidase activity showed a significant increase in cerebellum of aluminum exposed rats. Most of the above parameters responded moderately to the individual treatment with CA and HEDTA, but significantly reduced blood and brain aluminum burden. However, more pronounced beneficial effects on some of the above described parameters were observed when CA and HEDTA were administered concomitantly. Blood and brain aluminum concentration however, showed no further decline on combined treatment over the individual effect with HEDTA or CA. We conclude that in order to achieve an optimum effect of chelation, combined administration of CA and HEDTA might be preferred. However, further work is needed before a final recommendation could be made.     

Protective effect of zinc on liver injury induced byd-galactosamine in rats

The protective effects of zinc on liver injury induced byd-galactosamine (GalN) were investigated in rats in vivo and in vitro. Zinc supplementation (50 mg/kg/d) for 5 d of rats treated with GalN (1.5 g/kg, ip) could reduce their mortality rate, restore liver pathomorphological changes, maintain zinc content, inhibit the lipid peroxidation, hasten the protein synthesis, and improve liver function. In vitro, zinc supplement could abate the death of GalN-intoxicated hepatocytes, decrease malonaldehyde (MDA) content, and maintain reduced glutathione (GSH). It is concluded that zinc has protective effects on GalN-induced liver damage. Its effects may be owing to inhibition of lipid peroxidation and hastening of protein syntheses.     

Mechanosensitive ion channels in chara: influence of water channel inhibitors, HgCl2 and ZnCl2, on generation of receptor potential

Characean internodal cells generate receptor potential (ΔE _m) in response to mechanical stimuli. Upon a long-lasting stimulus, the cells generated ΔE _m at the moment of both compression and decompression, and the amplitude of ΔE _m at the moment of decompression, (ΔE _m)_E, was larger than that at compression. The long-lasting stimulus caused a membrane deformation (ΔD _m) having two components, a rapid one, (ΔD _m)_rapid, at the moment of compression and a slower one, (ΔD _m)_slow, during the long-lasting compression. We assumed that (ΔD _m)_slow might have some causal relation with the larger ΔE _m at (ΔE _m)_E. We treated internodal cells with either HgCl₂ or ZnCl₂, water channel inhibitors, to decrease (ΔD _m)_slow. Both inhibitors attenuated (ΔD _m)_slow during compression. Cells treated with HgCl₂ generated smaller (ΔE _m)_E compared to nontreated cells. On the other hand, cells treated with ZnCl₂ never attenuated (ΔE _m)_E but, rather, amplified it. Thus, the amplitude of (ΔD _m)_slow did not always show tight correlation with the amplitude of (ΔE _m)_E. Furthermore, when a constant deformation was applied to an internodal cell in a medium with higher or lower osmotic value, a cell having higher turgor always showed a larger (ΔE _m)_E. Thus, we concluded that changes in tension at the membrane may be the most important factor to induce activation of mechanosensitive Ca²⁺ channel.     

Purification and properties of human erythrocyte δ-amino-levulinic acid dehydratase (EC 4-2-1-24)

Human δ-aminolevulinic acid dehydratase (ALA-D) was purified 9 000-fold by salt precipitation, ion-exchange chromatography and gel filtration. These methods resulted into an electrophoretically and immunologically pure protein.The optimum pH of the enzyme is 6.6 and its Km with ALA : 4.8 × 10^?4 M. The enzymatic activity was increased by thiol-containing substances, such as dithiothreitol (DTT), which protect the -SH groups of the protein. Zinc, a portion of the enzyme molecule, was partly lost during the purification procedure; its addition enhances the enzymatic activity.Determination of molecular weights and electron microscopy study are in favor of an octameric structure.     

Protective effect of Lycium barbarum polysaccharides on streptozotocin-induced oxidative stress in rats

Fruit from Lycium barbarum L. in the family Solanaceae is well-known in traditional Chinese herbal medicine. Lycium barbarum polysaccharides (LBP) have been identified as one of the active ingredients responsible for its biological activities. We isolated polysaccharides from dried Lycium barbarum fruits by boiling water extraction. In the study, 50 animals were divided into two groups: a nondiabetic control (n = 10) and a diabetic group (n = 40). Diabetes was induced by a single injection of streptozotocin (50 mg/kg BW; Sigma, USA) freshly dissolved in a 0.1 mol/L citrate buffer (pH 4.5) into the intraperitonium. The normal control rats and the untreated diabetic control rats were only injected with the citrate buffer. Treated diabetic rats were administrated with LBP in drinking water through oral gavage for 30 days. At the end of experiment, oxidative indice in blood, liver and kidney of all groups were examined. The results show that administration of LBP can restore abnormal oxidative indice near normal levels. Therefore, we may assume that LBP is effective in the protection of liver and kidney tissue from the damage of STZ-induced diabetic rats and that the LBP may be of use as a antihyperglycemia agent.     

Protective effect of ginsenoside Rg3 on lung injury in diabetic rats

Ginsenoside has been used to treat diabetes, while ginsenoside Rg3 is the main active ingredient component of ginseng and is used to study its effects on lung tissue damage in diabetic rats. In this paper, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry were applied to detect the proliferation and apoptosis of BEAS-2B cells treated with different concentrations of Rg3. The inflammatory response and pathological change in the lung tissue of diabetic rats treated with Rg3 were evaluated by enzyme-linked immunosorbent assay, quantative real-time polymerase chain reaction, and hematoxylin and eosin staining immunohistochemistry. Meanwhile, PI3K and MAPK signaling pathway proteins in lung tissue were determined by Western blot analysis. The results showed that ginsenoside Rg3 had no significant influence on the proliferation and apoptosis of BEAS-2B cells. Ginsenoside Rg3 can inhibit inflammatory response and promote the activation of PI3K and MAPK signaling pathways to prevent damages of lung tissues induced by hyperglycemia. The protective effect provided by ginsenoside Rg3 indicates that ginsenoside Rg3 is a potential drug for the treatment of diabetes.     

Therapeutic potentials of combined use of DMSA with calcium and ascorbic acid in the treatment of mild to moderately lead intoxicated mice

The aim of this study was to explore the therapeutic efficacies of combined use of meso-2,3-dimercaptosuccinic acid (DMSA) with calcium and ascorbic acid in the treatment of mild to moderately lead-intoxicated mice. Female albino mice were exposed to lead by drinking water contaminated with 0.1% (moderate lead exposure) or 0.05% (mild lead exposure) lead acetate. After the cessation of lead exposure, mice were supplemented by gavage with saline solution, 50 mg/kg body weight (b.w) DMSA, 100 mg/kg b.w DMSA, calcium and ascorbic acid, or 50 mg/kg b.w DMSA and calcium as well as ascorbic acid, respectively. Atomic absorption spectrophotometric method was used to analyze lead levels in blood, bone, liver, kidney and brain. Activities of blood δ-aminolevulinic acid dehydratase (ALAD) were determined by colorimetric method. DMSA supplemented alone could reduce lead levels in both soft tissues and bone and reverse lead-inhibited activities of blood ALAD in mild to moderately lead-intoxicated mice. On the other hand, combined use of DMSA with calcium and ascorbic acid achieved better therapeutic efficacies in mobilizing lead in blood, liver and kidney, and reversing lead-inhibited activities of blood ALAD in moderately lead intoxicated mice than DMSA supplemented alone. Moreover, the better therapeutic efficacies were also found in mildly lead intoxicated mice in mobilizing lead in blood and bone achieved by combined use of DMSA with calcium and ascorbic acid. Combined use of DMSA with calcium and ascorbic acid seems to be the better choice in the treatment of mild to moderate lead-intoxication.     

Porphyrogenic effects and induction of heme oxygenase in vivo by δ-aminolevulinic acid

The effects of single large doses of the porphyrin-heme precursor ?d-aminolevulinic acid on tissue porphyrins and on δ-aminolevulinate synthase and heme oxygenase, the rate-living enzymes of liver heme synthesis and degradation respectively, were studied in the chick embryo in ovo, in the mouse and in the rat. δ-Aminolevulinic acid treatment produced a distinctive pattern characterized by extensive tissue porphyrin accumulation and alterations in these rate-limiting enzymes in the liver. Repression of basal or allylisopropylacetamide-induced liver δ-aminolevulinate synthase was observed and, in the mouse and the rat, induction of liver heme oxygenase after δ-aminolevulinic acid treatment, in a manner similar to the known effects of hemin on these enzymes. In the chick embryo liver in ovo heme oxygenase was substantially higher than in rat and mouse liver, and was not significantly induced by δ-aminolevulinic acid or other compounds, including hemin, CS₂ and CoCl₂. Levulinic acid, an analogue of δ-aminolevulinic acid, did not induce heme oxygenase in mouse liver. δ-Aminolevunilic acid treatment did not impair ferrochelatase activity but was associated with slight and variable decreases in liver cytochrome P-450. Treatment of chick embryos with a small ‘priming’ dose of 1,4-dihydro-3,5-dicarbethoxycollidine, which impairs liver ferrochelatase activity, accentuated porphyrin accumulation after δ-aminolevulinic acid in the liver. These observations indicate that exogenous δ-aminolevulinic acid is metabolized to porphyrins in a number of tissues and, at least in the liver, to a physiologically significant amount of heme, thereby producing an increase in the size of one or more of the heme pools that regulate both heme systhesis and degradation. It is also possible than when δ-aminolevulinic acid is markedly overproduced in vivo it may be transported to many tissues and re-enter the heme pathway and alter porphyrin-heme metabolism in cells and tissues other than those in which its overproduction primarily occurs.