Nephrocytomegaly Kidney Toxicity in VS .NET

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Nephrocytomegaly Kidney Toxicity
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Feeding alkali-treated proteins to rats induces changes in kidney cells. These changes are characterized by enlargement of the nucleus and cytoplasm and disturbances in DNA synthesis and mitosis. These lesions, which have been attributed to LAL (15, 144 152), are designated as nephrocytomegaly (karyomegaly). The affected cells are epithelial cells of the straight portion (pars recta) of the proximal renal tubules (Fig. 6.1.11). Enlarged nuclei tend to have more than the diploid complement of DNA, unusual chromatin patterns, and proteinaceous inclusions. Increases in total nonchromosomal protein parallel increases in nuclear volume. These events suggest disruption of normal regulatory function of the pars recta cells. The renal tubular epithelial kidney cells of all animals increased in both size and in DNA content. Necrosis of the cells was characterized by cytoplasmic edema and vacuolization, loss of microvilli, and increased lysosomal and cytoplasmic inclusions. -Aminoalanine, ornithinoalanine, and phenylethylaminoalanine induced similar rat kidney lesions at higher doses
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DIETARY SIGNIFICANCE OF PROCESSING-INDUCED LYSINOALANINE
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Figure 6.1.11 Photomicrographs of outer medullary stripe of kidneys from rats fed 20% soy protein diets for 8 weeks: (a) control diet; note uniformity of pars recta cells; (b) alkali-treated protein (2630 ppm of dietary LAL); note cytoplasmic and nuclear enlargement of the pars recta cells. Adapted from Reference 144.
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than did LAL (15, 32). The amount of LAL required for induction of cytomegaly in rats was similar to that present in some commercial foods (Table 6.1.1). The cytomegaly was partly reversed following discontinuance of the alkali-treated soy protein diets. A dif culty in formulating a simple relationship between LAL and nephrocytomegaly is that proteins of equal LAL content produce different biological responses. Thus, O Donovan (153) reported that feeding rats alkali-treated soy protein led to severe nephrocytomegaly, while a different protein with the same LAL content did not produce lesions. Alkali-treated soy protein (supplying 1400 2600 ppm LAL) induced nephrocytomegaly, whereas 2500 ppm LAL derived from alkali-treated lactalbumin did not (146). Generally, free LAL is a much more potent inducer of kidney damage than is the same concentration of protein-bound LAL. The divergent observations about relative potencies of various alkalitreated proteins in inducing kidney lesions could arise from dietary factors and from the combined effects of other kidney-damaging compounds present in the diet. Because D-Ser is formed concurrently with LAL, and since it also induced kidney lesions (154, 155), serine may potentiate the action of LAL. This aspect is examined in more detail in 6.2 on D-amino acids. The mechanism of the observed cellular action of LAL is not well understood. Based on the observed inhibition of metalloenzymes by LAL and the observed high af nity of copper ions for LAL and metalloenzymes, Pearce and Friedman (17) suggested that the damage observed in the proximal tubules probably arises from interaction of LAL with copper(II) of metallothioneins within epithelial cells. Generally, LAL may interfere with the mechanism by which the kidney conserves copper by displacing histidine as the major lowmolecular-weight carrier of copper in vivo. The observed high speci city of the LAL effect for the rat kidney is probably due to the fact that nephrotoxicity in the rat is related to the high content
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NUTRITION AND SAFETY
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of L-amino acid oxidase activity (which presumably catalyzes the formation of LAL metabolites responsible for toxicity) compared with other species evaluated (156). In addition to the rat (minimum-nephrotoxic-effect concentration [MNEL] = 100 ppm LAL) and the mouse (MNEL = 1000 ppm LAL), nephrocytomegaly was not observed in the kidneys of hamsters, dogs, Rhesus monkeys, rabbits, and Japanese quail fed up to 10,000 ppm LAL for 4 to 9 weeks (15, 121, 157, 158). LAL competitively inhibited lysyl-tRNA-synthetase of prokaryotic and eukaryotic cells. It was incorporated into proteins and inhibited incorporation of lysine by a cell-free eukaryotic protein-synthesizing system (159). Whether these actions at the cellular concentration are relevant to the induction of nephrocytomegalia is not known. 6.1.6.5 Chelation of Metal Ions
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Because the structure of LAL contains two amino, one imino, and two carboxyl groups, which can participate in acid-based equilibria (Fig. 6.1.12) and serve as potential metal ion-chelating sites (Fig. 6.1.13), our research suggests, as mentioned earlier, that some of the biological properties of the molecule may be due to metal ion chelation (7, 20, 160). This prediction was later con rmed by several investigators (130, 133, 161 164). In vivo studies con rmed expectations from the in vitro results. LAL and Maillard products complexed with essential trace elements and enhanced renal resorption and excretion of copper in rats. The resorption-excretion was less pronounced with iron and zinc. To further demonstrate this possibility, we have examined LAL (a mixture of the LD- and LL-isomers as well as the individual isomers) for its af nity toward a series of metal ions, of which copper(II) was chelated the most strongly (Fig. 6.1.13). On this basis, we have suggested a possible mechanism for kidney damage in the rat involving LAL interaction with copper within the epithelial cells of the kidneys. As we described in detail elsewhere (16, 17), it is possible to determine pK values of LAL amino, imino, and carboxyl groups (Fig. 6.1.12), metal ionbinding constants of LAL isomers, and to predict the in vivo equilibria between histidine, the major low-molecular-weight copper carrier in plasma, and competing chelating agents such as LAL. A mathematical analysis was used to predict LAL plasma concentrations needed to displace histidine as the major copper carrier in vivo. The calculated values were 27 M for LD-LAL, 100 M for LL-LAL, and 49 M for the mixture of the two. LD-LAL would be a better competitor for copper(II) in vivo than the LL-isomer, that is it will take about one-fourth as much LD-LAL as LL-LAL to displace the same amount of histidine from copper histidine. This difference could explain the greater observed toxicity of LD-LAL (15). The apparent direct relationship between the observed af nities of the two LAL isomers for Cu+2 ions in vitro and their relative toxicities in the rat kidney is consistent with our hypothesis that LAL
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OOC CH CH2 1.3 NH2+ CH2 HOOC CH CH2 NH2+ CH2 CH2 CH2 CH2 HOOC CH (a) NH 3 NH3 CH2 CH2 CH2 HOOC CH (b) HOOC CH CH2 NH2+ CH2 2.2 CH2 CH2 CH2 OOC CH (c) NH3 NH3 NH3 OOC CH CH2 NH2+ CH2 CH2 CH2 CH2 OOC CH (d) 1.3 NH3 NH3 NH3 2.2 OOC 7.1 CH CH2 NH2+ CH2 CH2 CH2 CH2 HOOC CH (e) OOC CH CH2 NH CH2 7.1 CH2 CH2 CH2 OOC CH (f) NH3 9.7 9.2 NH3 OOC CH CH2 NH CH2 CH2 CH2 CH2 NH3 HOOC CH (g) 9.2 NH3 OOC CH CH2 NH CH2 CH2 CH2 CH2 OOC CH (h) NH2 NH3 NH3 OOC CH CH2 NH CH2 CH2 CH2 CH2 OOC CH (i) 9.2 NH2 NH
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K1 = [H4LAL][H]/[H5LAL] = ([b] + [c])[H]/[a] = [b][H]/[a] + [c][H]/[a] = k1 + k4 = 10-1.3 + 10-2.2 = 10-1.25 (data from above figure) pK1 = 1.25 1/K2 = [H4LAL]/[H][H3LAL] = ([b] + [c])/[H][d] = [b]/[H][d] + [c]/[H][d] = 1/k14 + 1/k41 = 10+1.3 + 10+2.2 = 10+2.25 pK2 = 2.25 K3 = [H2LAL][H]/[H3LAL] = ([e] + [f])[H]/[d] = [e][H]/[d] + [f][H]/[d] = k142 + k143 = 10-7.1 + 10-7.1 = 10-6.8 pK3 = 6.8 K4 = [HLAL][H]/[H2LAL] = ([g] + [h]) X [H]/([e] + [f]) = ([g][H] + [h][H])/([e] + [f]) = ([f]kl342 + [f]kl345)/([g][H]/k1243 + [g][H]/k1342) = [f](k1342 + k1345)/[(l/kl243 + l/kl342)[f]kl342] = (k1342 + k1345)/[(1/k1243 + 1/k1342)k1342] = (10-9.2 + 10-9.7)/[(10+9.2 +10+9.2) X 10-9.2] = 10-9.4 pK4 = 9.4 1/K5 = [HLAL]/[H][LAL] = ([g] + [h])/[H][i] = [g]/[H][i] + [h]/[H][i] = 1/k12345 + l/k13452 = 10+9.7 + 10+9.2 = 10+9.8 pK5 = 9.8
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Figure 6.1.12 Acid base ionization equilibria of lysinoalanine. Adapted from Reference 17. The determined pK values were used to determine LAL af nities to metal ions (16, 17).
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