Tbe Presence of a2u-Globulin Is Necessary for d-Limonene Promotion of Male Rat Kidney Tumors
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چکیده
There is a growing list of chemieals that induce a male rat specific renal disease, known as (Y2u-G nephropathy (1). Neither female rats nor either sex of mice, guinea pigs, dogs, or monkeys develop this renal disease upon exposure to these chemicals (13). The acute stage of a2u-G nephropathy is characterized by an accumulation of protein droplets in lysosomes of the P2-segment of the proximal convoluted tubules (4-8). These protein droplets have been shown to contain accumulations of a2u-G using immunohistochemistry (9-11). a2u-G, a low molecular weight M r 18,700 protein, is synthesized under androgenic control by the hepatic parenchymal cells in mature male rats, secreted into the blood, and excreted in large amounts (3-19 mgjday) via the urine (12-15). a2u-G is also found in the urine of female rats, however, at concentrations between 107and 680-fold lower than those excreted by the male rat (15). In addition, the female rat does not synthesize the hepatic form of a2u-G, which makes up the bulk of the urinary a2u-G found in male rats. In contrast to the commonly used F344 or Sprague-Dawley male rats, the inbred NBR male rat does not synthesize the androgen-dependent a2u-G (16). These authors proposed that the lack of androgenic induction of a2u-G in the liver of NBR rats is the result of a tissueand gene-specific regulatory defect, since no endocrinological or reproductive abnormalities are apparent in these animals, and the mRNA for the androgenrepressible hepatic protein, SMP-2, is normally regulated. NBR rats acutely exposed to chemicals that cause (Y2u-G nephropathy such as dL, TMP, UG, isophorone, 1,4-dichlorobenzene, lindane, and decalin do not develop the disease (1 1, 17). This suggests that the presence of (Y2u-G is aprerequisite for the induction of this syndrome. Indeed, chemieals such as dL, TMP, 1,4-dichlorobenzene, and isophorone andjor their metabolites were shown to be bound reversibly to (Y2u-G after in vivo or in vitro exposure (1821). In in vitro studies, the a2u-G-chemical complex proved to be less degradable by endopeptidases than (Y2u-G alone, suggesting that a decrease in lysosomal degradation is involved in the accurnulation of a2u-G in male rat kidney lysosomes (22). Continued exposure to chemicals causing (Y2u-G nephropathy leads to accumulation of a2u-G, degeneration, necrosis, and sloughing of individual cells lining the P2-segment of the proximal tubule, and increased rates of cell replication (6, 7, 11, 19, 23-25). Short et al, (25) proposed that reduced cell function and eventual cell death may result from the combination of lysosomal dysfunction, release of digestive enzymes into the cytoplasrn, and decreased plasma membrane availability and turnover. The observed increase of cell replication rates was suggested to be a compensatory reaction of the kidney to the sustained cellloss (3, 6). Chronic exposure to a2u-G nephropathy inducing agents results in a low but significant incidence of renal tumors in male rats, but not in fernale rats or either sex of mice (1, 26-32). A previous initiation-promotion bioassay revealed that chronic exposure to UG and TMP resulted in accumulation of a2u-G, elevated cell proliferation, and cytotoxicity in the P2-segment of the male rat proximal tubules, whereas female rats were unaffected (25). In addition, significantly increased incidences of preneoplastic lesions and renal tumors were observed in male, but not in female rats promoted with UG or TMP. These 3512 ABSTRACT
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تاریخ انتشار 2001