1.
Asp, Vendela, et al.
(författare)
Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
2010
Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 242:3, s. 281-289
Tidskriftsartikel (refereegranskat) abstract
The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.
2.
Öhrvik, Helena, et al.
(författare)
Cadmium Transport in a Model of Neonatal Intestinal Cells Correlates to MRP1 and Not DMT1 or FPN1
2013
Ingår i: ISRN Toxicology. - : Hindawi Limited. - 2090-6188 .- 2090-6196. ; 2013, s. 1-9
Tidskriftsartikel (refereegranskat) abstract
Newborns have a higher gastrointestinal uptake of cadmium than adults. In adults, the iron transporters DMT1 and FPN1 are involved in the intestinal absorption of cadmium, while in neonates, the mechanisms for cadmium absorption are unknown. We have investigated possible cadmium transporters in the neonatal intestine by applying a model of immature human intestinal epithelial Caco-2 cells. To mimic the continuous cadmium exposure via diet in neonates, cells were allowed to differentiate for 7 days in medium containing 1 μM CdCl2. A dramatic upregulation of the MT1 gene expression followed cadmium pretreatment, indicating a high sensitivity of the immature cells to cadmium. Cadmium pretreatment increased the basolateral efflux of109Cd, without causing any effects on the passive diffusion of mannitol or the transepithelial electrical resistance. The augmented transport of cadmium was correlated to an upregulation of MRP1 gene expression and increased activity of the efflux protein MRP1. No effects were observed on gene expression of the efflux proteins MRP2 and P-gp or the iron transporters DMT1, DMT1-IRE and FPN1. In conclusion, our data indicate that continuous cadmium exposure increases the absorption of the metal in immature intestinal cells and that MRP1 is involved in the intestinal cadmium absorption in newborns.
3.
Oskarsson, Agneta
(författare)
Chapter 60. Vanadium
2014
Ingår i: Handbook on the Toxicology of Metals. - 9780444594532 ; , s. 1347-1367
Bokkapitel (övrigt vetenskapligt/konstnärligt) abstract
Absorption of vanadium from the gastrointestinal tract is poor, not exceeding 2% in humans. Soluble compounds of vanadium are absorbed to a considerable extent after inhalation and concentrated in the lung, but available information is not adequate for a reliable estimation of dose-response relationships. Absorbed vanadium is widely distributed in the body. In animals, the highest values are found in the bone, kidney, liver, and spleen. Bone maintains essentially unchanged levels for several weeks. Low concentrations have been detected in the brain, and in animal placenta and testes. Urine is the predominant route of excretion of absorbed vanadium. Animal and human data indicate that excretion occurs in at least two phases. A three-compartment model for elimination is described in humans, with half-times after intravenous injection of 1.2h, 26h, and 10-12 days. Vanadium is essential for certain bacteria and microorganisms. Some reports suggest that vanadium is essential for mammals, but no biochemical function has been defined in humans. The total dietary intake is estimated to be 6-30μg/day, and in some regions up to 50μg/day. The use of vanadium as a supplement for athletes and body builders has been reported. Point-of-contact non-neoplastic and neoplastic effects in experimental animals occur in the respiratory tract. Systemic effects have been observed in the liver, kidney, nervous system, cardiovascular system, and blood-forming organs. Metabolic effects include interference with the biosynthesis of cystine and cholesterol, depression and stimulation of phospholipid synthesis, and, at higher concentrations, inhibition of serotonin oxidation. Vanadate has been shown to inhibit sodium/potassium-transporting ATPase (Na+/K+ATPase), phosphatases, and several other enzyme systems. Vanadium compounds enhance the effects of insulin and have been shown to lower blood glucose in experiments in diabetic animals and humans. Both acute and chronic effects of occupational exposure to vanadium pentoxide (V2O5) and other vanadium compounds have been described. They are manifested mainly as delayed but reversible irritation of the respiratory tract involving excess mucus production and prolonged coughing, accompanied in cases of more severe exposure by bronchospasm, wheezing, and diarrhea. Eye irritation and conjunctivitis have been reported in workers. Tracheobronchitis may result from heavy, long-term exposure. Changes in lung function indicating obstructivity and increases in inflammatory biomarkers have been demonstrated in boiler cleaners after prolonged exposure. Vanadium is not mutagenic in the Ames test. However, pentavalent and tetravalent vanadium compounds have produced aneuploidy in somatic cells invitro and invivo. Clear evidence of carcinogenic activity has been shown in mice after inhalation of V2O5. The International Agency for Research on Cancer has classified V2O5as a possible carcinogen (Group 2B). Biological monitoring of vanadium in serum, blood, and urine is used to assess exposure to vanadium compounds in occupational and population studies. Reviews on environmental, toxicological and occupational health aspects of vanadium and vanadium compounds have been published (143,93,12,54,219,95,15,90,59,91,88,89and97).
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