Lead is one of the metals whose toxicological effect in humans and animals is of clinical concerned as reported by researchers. Quite a number of chemical agents have been reported to ameliorate lead associated toxicological effects especially in animal studies. This literary study reviewed reported toxicological effect of lead on the liver, kidney and brain with emphasis on the roles of mitigating chemical agents. In this review it was observed that his to patho logical changes in lead associated he patotoxicity include hepatomegaly with necrosis, formation of hyper plastic nodules and presence of in tranu clear inclusion bodies within hepatocytes. In the kidney reports revealed various degenerative changes with focal tubular necrosis invaded by inflammatory cells in cortical renal tubules, diminution in the amount of filtration slits, apoptosis in epithelial cells of the glomeruli, increase in lysosomal structures, pinocytic vesicles and large mitochondria in proximal tubule cells. Lead altered mRNA levels of the following apoptotic and neurotrophic factors: caspase 2 and 3 and brain-derived neurotrophic factor in the brain. Histopathological changes occurred in gray matter, anterior cingulate cortex, hippocampus and cerebellum of treated animals. Lead exposure altered biomarkers of liver, kidney and brain function with increased lipid peroxidation and decrease antioxidants function. Lead induced toxicities were observed to be mitigated by vitamin C, vitamin E, calcium, magnesium dimercaptosuccinic acid, calcium disodium ethyl diaminetetra acetic acid and selenium. Extracts of plant origin and chemical substances of animal origin were also reported to mitigate these toxicities. One of the commonly reported mechanisms associated with lead toxicological effect is the generation of Reactive Oxygen Species in organs and tissues this may be supported by the mitigating effect of some antioxidants on lead toxicological effects.

There are increasing reports on cadmium associated hepatotoxicity, due to these reports this study reviewed relevant literature on cadmium associated hepatotoxicity with emphasis on doses, route of administration, salt forms (cadmium compounds) and the roles of mitigating agents. Reports have shown that continuous exposure of the liver to cadmium has led to hepatotoxicity. Humans are generally exposed to cadmium by two main routes, inhalation and ingestion. In this study, evaluation of relevant literature showed that irrespective of route of administration and salt forms cadmium hepatotoxicity is dose and time dependent. Cadmium associated hepatotoxicity manifested through impaired functions of hepatic biomarkers (transaminases), enzymatic and non enzymatic antioxidants. Histopathological damage to liver architecture manifested as swelling of hepatocytes, focal necrosis, hepatocytes degeneration, dilatation of ribosomes, damage of membrane-bounded lysosomes, nuclear pyknosis and cytoplasm vacuolization. Deterioration of mitochondrial cristae, deposition of collagen fibrils, hypertrophy of kuffer cells, congestion in central veins and sinusoids, infiltration of mixed inflammatory cells and peripheral hemorrhage also occurred. Hepatotoxic effect of cadmium was mitigated by Vitamin C, Vitamin E, Manganese (11) Chloride, N-acetylcysteine and Selenium. Extracts of plant origin including Solanum tuberosum, Calycopteris floribunda and Hibiscus sabdariffa mitigated cadmium induced hepatotoxicity. Chemical substances of animal origin including honey and camel milk were reported to have ameliorated cadmium induced hepatotoxicity. One of the mechanisms of cadmium induced hepatotoxicity is reported to be associated with the up regulation of reactive oxygen species (oxidative stress) which caused oxidative damage to lipid contents of membranes and direct liver injury. Conclusion cadmium is dose and time dependently hepatotoxic irrespective of route of administration, salt form and is ameliorated by some antioxidants and extracts of plant and materials of animal origin which may require further evaluation for clinical application.

Tenofovir is one of the most commonly used antiretrovirals in adolescents and adults because of its potency and favorable pharmacokinetic and relative safety toxicological profile. It has been combined successfully with antiretroviral drugs from classes such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors to achieve virologic suppression in a high percentage of recipients. Despite its therapeutic success, quite a number of cohorts and clinical studies have associated tenofovir with the development of renal toxicity with few studies on the opposing end. This stimulated us to review reported cohorts and clinical studies on tenofovir renal toxicity. In this study it was observed that literature reported incidence of tenofovir renal toxicity falls within the range of 0.7% -17%. Available studies gave different appellations to tenofovir renaltoxicity, which include fanconis syndrome, proximal tubule dysfunction, acute renal failure, chronic renal failure, chronic kidney disease and nephrogenic diabetes insipidus. Markers of renal toxicity (tubulopathy) which include glycosuria, hyperaminoaciduria, proteinuria, hyperphosphaturia, hyperuricosuria, retinol-binding protein, beta2-microglobulinuria, decreased creatinine clearance and decreased glomerular filtration rate were also reported. In some studies renal biopsy demonstrated cytoplasmic vacuolization, apical localization of nuclei and reduction of the brush border on proximal tubule epithelial cells. This study observed that tenofovir renal toxicity could be reversible on discontinuation of tenofovir therapy despite contrary views by some studies. Regardless of tenofovir reported renal toxicity, it is well tolerated with a relative safety profile but it is advised that renal profile of patients should be evaluated before and routinely during tenofovir therapy.

Antiretroviral drugs are used for the treatment of human immunodeficiency virus, they are used as combination regimens to achieve the highest possible benefit, tolerability, compliance and to diminish the risk of resistance development. Reports from preclinical and clinical studies have linked antiretrovirals with some toxicological effects which could be associated with redox imbalance (oxidative stress). This stimulated us to review relevant literature on the relationship between antiretroviral induced toxicological effects and redox imbalance. Available literature on antiretroviral associated toxicological effects and oxidative stress were comprehensively reviewed. Literature showed that antiretrovirals are associated with toxicological effects which includes hepatotoxicity, cardiotoxicity, hematotoxicity and nephrotoxicity. Reports in animal studies also showed that these toxicological effects could be associated with oxidative stress through the generation of oxidative radicals, depletion of antioxidants and antioxidant enzymes leading to mitochondria damage in the heart, kidney, liver brain and other organs. In humans, studies also showed that antiretrovirals are associated with lipid peroxidation, depletion of antoxidants and antioxidant enzymes which are elements of oxidative stress. Furthermore it was observed that supplementations with some antioxidants mitigated antiretroviral induced oxidative stress, mitochondria damage and toxicological effects. Antiretroviral drugs are associated with toxicological effects which may involve redox imbalance, but more studies are required to correlate antiretroviral toxicities with oxidative stress.

Tenofovir is a nucleotide reverse transcriptase inhibitor used as part of antiretroviral regimens. It is well tolerated with relative toxicological effects but recent reports have linked it with renal toxicity which is of clinical concern. This study reviews literary work on tenofovir renal toxicity with more light on case reports. Tenofovir renal toxicity manifests as Fanconi's syndrome, nephrogenic diabetes insipidus and acute renal failure. Fanconi's syndrome is characterised by acidosis, protenuria, albuminuria, aminoaciduria, hyperchloremic, metabolic acidosis, hypouricemia, hypophosphatemia and glycosuria. The presence of urine osmolality, polydipsia and polyuria could give credence totenofovir induced nephrogenic diabetes insipidus. In some cases of tenofovir renal toxicity, renal biopsy revealed sclerosed glomeruli with ischemic injury including portal collapse of capillary loops. Histopathological changes in glumeruli include mild mesangial proliferation, increased mesangial matrix and thickened capillary loops. Moderate degenerative tubular changes, loss of tubular mass, interstitial scarring and scattered cellular infiltrates. Pharmacodynamic and pharmacokinetic interactions may occur with the co administration of tenofovir with non steroidal anti-inflammatory drugs, aminoglycosides and some protease inhibitors which may potentiate renal toxicity. Tenofovir renal toxicity is associated with some risk factors including genetic polymorphism as supported by dichotomy in renal toxicity among different race and the association between ABCC2 gene and tenofovir kidney tubular dysfunction. The pharmacology of tenofovir renal toxicity is unclear but it is attributed to the interaction between tenofovir and theorganic anion transporters (hOAT1, and to a lesser extent, OAT3) favoring intracellular accumulation in renal proximal tubule cells. This may lead to ultrastructural mitochondrial abnormalities and decreased mtDNA levels which could stimulate reactive oxygen species production, depletion of antioxidants and antioxidant enzymes. These processes can stimulate the destruction of biomolecules such as DNA, proteins, and lipids, thus causing the deregulation of redox-sensitive metabolic pathways, signaling pathways, and cell death. Despite tenofovir renal toxicity it has achieved notable therapeutic success nevertheless patients on tenofovir containing regimens should be monitored for renal function parameters. Co administration with potential nephrotoxic drugs should be avoided except when benefit outweighs risk.