Macromolecular adducts

Both the retention time of the paramagnetic complex in the vasculature and the relaxivity increase resulting from the slower rotation of the macromolecular adduct will depend on the... 

The latter point is rather critical. In fact, whereas long xr values can be easily attained through a proper choice of the macromolecular system and the binding modality, it may not be an easy task to keep the relaxometric properties of the paramagnetic moiety unaltered, upon formation of the macromolecular adduct. In fact, this may result in a reduced hydration of the Gd(III) ion as donor groups such as aspartate or glutamate on the surface of a protein can replace coordinated water molecules (103 104). When the hydration state is maintained, the occurrence of a marked reduction of the exchange rate of inner-sphere water is very common (see next Section). 

In terms of chimeric macromolecules, the backbone of the oxidized protein or peptide can be extended by means of a mono-aminooxy functionalized protein, or a similar derivative of a nonprotein polymer (macromolecular adducts, see below). As an exercise in site-... 

Gamier, R., Rambourg-Schepens, M.O., Muller, A. Hallier, E. (1996) Glutathione transferase activity and formation of macromolecular adducts in two cases of acute methyl bromide poisoning. Occup. environ. Med., 53, 211-215... 

Many commonly measured pharmacokinetic values can be used as biomarkers of exposure. Examples include parent compound or metabolites in exhaled breath, blood, or urine and macromolecular adducts or their degradation products that appear in urine. To make quantitative assessments of the relationship of such markers to prior exposures, it is necessary to determine the rate of formation and removal (clearance) of the marker. From this information it is possible to predict the steady-state concentrations of the marker following various exposure scenarios. In addition, with information on the rate of formation and removal of a marker and knowledge of the factors that influence those rates (such as gender, dose, repeated exposures, route of exposure, rate of exposure), a mathematical model that describes the concentration of the marker under different exposure conditions can be developed. While the concentration of the marker cannot be used to identify a unique exposure scenario, the marker can indicate the types of exposure regimens that would produce the measured level of the biomarker. 

Poirier MC, Santella RM, and Weston A (2000) Carcinogen macromolecular adducts and their measurement. Carcinogenesis 21 353-359. 

Turteltaub, K.W. et al., Macromolecular adduct formation and metabolism of heterocyclic amines in humans and rodents at low doses, Cancer Lett., 143, 149, 1999. 

Weston A, Rowe M, Poirier M, et al. 1988. The application of immunoassays and fluorometry to the detection of polycyclic hydrocarbon-macromolecular adducts and anti-adduct antibodies in humans. Int Arch Occup Environ Health 60(3) 157-162. 

By comparison, collection of blood/plasma is more invasive and should be performed by trained medical personnel. These samples offer potential benefits in that both unbounded metabolites and the more long-lived macromolecular adducts can be assayed. However, blood is more difficult to prepare for analysis. 

Table 13.16 Macromolecular Adducts as a Class of Toxic Metabolites (21)...

Macromolecular adducts may be toxic due to loss of the macromolecule s original functions antigenic activity toxic breakdown products... 

Cheever KL, DeBord DG, Swearengin TF. 1991.4,4 -Methylenebis(2-chloroaniline) (MOCA) The effect of multiple oral administration, route and phenobarbital induction on macromolecular adduct formation in the rat. Fundam AppI Toxicol 16(1) 71-80. 

Cheever KL, Richards DE, Weigel WW, et al. 1988. Macromolecular adduct formation by 4,4 methylene-bis(2-chloroaniline) in adult male rat. Scand J Work Environ Health 14 57-59. 

Weston, A. Newman, M. Vahakangas, K. Rowe, M. Trivers, G. E. Maim, D. L. Harris, C. C. Measurement of carcinogen-macromolecular adducts and serum antibodies recognizing DNA adducts in biological specimens firom people exposed to chemical carcinogens. Environ. Sci. Res., 36 91-101. 1987. 

Accelerator mass spectrometry (AMS) has long been used for quantifying concentrations of metabolites in humans, primarily for activated metabolites of environmental compounds that form genotoxic macromolecular adducts (Turteltaub et al., 1993, 1997, 1999 Dingley et al., 1999 Mauthe et al., 1999 Lightfoot et al., 2000 Cupid et al., 2004) agrieultaural chemicals that chronically... 

The formation of macromolecular adducts could be partly responsible for the increase in depuration half-life observed following increased periods of exposure of molluscs to the xenobiotic, particularly for PAH and other hydrocarbons (see Sect. 7.1). The process of adduct formation, and presumably excision and release, could therefore represent, or contribute to, the more stable cellular compartment with a lower rate of xenobiotic turnover postulated by Stegeman and Teal (1973). Similar considerations could contribute to, or explain, the observed tenfold excess in bis(tributyltin) oxide accumulation, compared to that predicted, in M. edulis (Laughlin et al 1986) the preferential retention of PCB with increasing degrees of chlorination (Sect. 7.1) and the higher BCF of PCB compared to those of PAH of similar n-octanol/water partition co-efficients (Pruell et al. 1986). 

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