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- Bergdahl, Ingvar A., et al.
(författare)
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Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes
- 1997
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Ingår i: Basic and Clinical Pharmacology and Toxicology. - : Wiley. - 0901-9928. ; 81:4, s. 153-158
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Tidskriftsartikel (refereegranskat)abstract
- Over 99% of the lead present in blood is usually found in erythrocytes. To investigate the nature of this selective accumulation of lead in erythrocytes, the specific binding of lead to proteins in human erythrocytes was studied using liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP-MS). The principal lead-binding protein had a mass of approximately 240 kDa, and adsorption to specific antibodies showed that protein was delta-aminolevulinic acid dehydratase (ALAD). Thus, the previous notion that lead in erythrocytes was bound primarily to haemoglobin has to be revised. Furthermore, in lead-exposed workers, the percentage of lead bound to ALAD was influenced by a common polymorphism in the ALAD gene. Specifically, in seven carriers of the ALAD2 allele, 84% of the protein-bound lead recovered was bound to ALAD compared to 81% in seven homozygotes for the ALAD1 allele whose erythrocytes were matched for blood-lead concentration. The small difference was statistically significant in Wilcoxon matched-pairs signed-rank test (P = 0.03). No ALAD allele-specific difference in ALAD-bound lead was found among 20 unexposed controls. Perhaps the difference in ALAD-bound lead can provide an explanation for the previously reported finding of higher blood-lead levels among carriers of the ALAD2 allele than among ALAD1 homozygotes in lead-exposed populations.
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- Johansson, Maria, et al.
(författare)
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Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
- 1998
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Ingår i: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 83:5, s. 225-230
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Tidskriftsartikel (refereegranskat)abstract
- The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.
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- Luurila, S., et al.
(författare)
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Pharmacokinetics of bisphosphonates in rabbits
- 1999
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Ingår i: Pharmacology and Toxicology. - : Blackwell Munksgaard. - 0901-9928 .- 1600-0773. ; 84:1, s. 24-28
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Tidskriftsartikel (refereegranskat)abstract
- Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The 14C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P<0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P=0.016). At 24 hr, plasma concentration of tiludronate was 12 ± 6.6%, of etidronate 18 ± 2.5%, of clodronate 0.8 ± 0.2%, and of pamidronate 1.4 ± 0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC(0-24hr) for tiludronate and etidronate was 9-11 times larger than for clodronate. AUC(0-24hr) for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9- 15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2-1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of filudronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.
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