A comparative study on serologic profiles of virus hepatitis B.
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Biomedical subjects
Publications and source records attributed to C J Jin.
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We present a model for perfusion of the isolated perfused neonatal sheep liver which allows examination of drug disposition by the intact organ. We studied the disposition of sodium taurocholate (TC) in seven neonatal lambs (ages 2-11 days) and compared the results with earlier data from the perfused fetal sheep liver (Ring, J. A. et al. Biochem. Pharmacol. 1994, 48, 667-674). Measurements of perfusion pressure, oxygen consumption, lactate:pyruvate ratio, bile flow, and liver histology indicated that the preparation was both viable and stable over a 2 h period. [14C]-labeled TC was added to the reservoir by constant infusion (30 micromol/h) and the ductus venosus shunt quantitated by injection of [153Gd]-labeled microspheres. Shunt-corrected hepatic extraction ratio of TC was 0. 56 +/- 0.14 (fetal 0.23 +/- 0.16, p < 0.005) and clearance of TC was 0.92 +/- 0.35 mL/min/g liver (fetal 0.44 +/- 0.23 mL/min/g, p < 0. 01). We conclude that the isolated perfused neonatal sheep liver is a useful experimental model which will facilitate the study of the developmental physiology and pharmacology of the liver. There is considerable maturation of the biliary excretion of TC between the late fetal and early neonatal periods in the lamb.
The capacity of two human hepatic UDP-glucuronosyltransferase (UGT) isoforms, UGT2B7 and UGT2B11, to metabolize more than 50 hydroxylated androgens and pregnanes was investigated. All mono- and dihydroxylated androgens with a hydroxyl function in the 3 alpha, 6 alpha, and 17 beta positions were glucuronidated by UGT2B7, but highest activity was generally observed for steroids containing a 3 alpha-hydroxy substituent. UGT2B7 did not glucuronidate 2 alpha-, 2 beta-, 3 beta-, 6 beta-, 7 alpha-, 11 alpha-, and 11 beta-monohydroxylated androgens, although the presence of hydroxyl groups at certain of these positions did not abolish the ability of UGT2B7 to metabolize diols which also possessed a 3 alpha- or 17 beta-hydroxyl group. 3 alpha-Hydroxypregnanes were also glucuronidated by UGT2B7. Activity was not detected for 6 alpha-, 6 beta-, 11 beta-, 12 alpha-, 16 alpha-, 17 alpha-, 20 alpha-, or 21-monohydroxylated pregnanes. Although 11 alpha-hydroxylated androgens were not glucuronidated by UGT2B7, this enzyme exhibited high activity toward the 11 alpha-hydroxylated derivatives of 5 beta-prenanedione and progesterone. UGT2B11 similarly glucuronidated 3 alpha-hydroxyandrogens and -pregnanes, but rates of metabolism were low compared to UGT2B7. With the exception of androsterone and its 5 beta-isomer, ring A/B stereochemistry appeared not to influence rates of hydroxysteroid glucuronidation by UGT2B7 and UGT2B11. Overall, the data indicate a high degree of stereo- and regioselectivity in the glucuronidation of hydroxyandrogens and -pregnanes by UGT2B7 and UGT2B11 and further suggest that UGT2B7 may contribute to the glucuronidation of 3 alpha-hydroxysteroids in humans.
Two new UDP-glucuronosyltransferase cDNAs, designated UGT2B10 and UGT2B11, encoding 528 amino acid proteins were isolated from a human liver cDNA library. The deduced amino acid sequences of UGTs 2B10 and 2B11 share > 76% sequence similarity with other known human liver UGT2B subfamily isoforms and < 48% sequence similarity with UGT1 family proteins. COS-7 cells transfected with UGT 2B10 and 2B11 synthesized proteins with respective molecular masses of 49kDa and 51kDa. UGT2B11 expressed in COS-7 cells glucuronidated a number of polyhydroxylated estrogens (estriol, 4-hydroxyestrone and 2-hydroxyestriol) and xenobiotics (4-methylumbelliferone, 1-naphthol, 4-nitrophenol, 2-aminophenol, 4-hydroxybiphenyl and menthol). Despite the screening of more than forty potential substrates, glucuronidation activity was not observed for expressed UGT2B10.
The capacity of four cDNA-expressed human liver UDP-glucuronosyltransferases (UGT), UGT1*6, UGT2B7, UGT2B10 and UGT2B11, to glucuronidate hydroxylated metabolites of benzo[a]pyrene (B[a]P) and 2-acetylaminofluorene (AAF) has been investigated. UGT1*6 and UGT2B7 glucuronidated a range of B[a]P and AAF metabolites with a degree of regiospecificity, although UGTs 2B10 and 2B11 were inactive towards all compounds screened. UGT2B7 glucuronidated the B[a]P trans 4,5- and 7,8-dihydrodiols and the 1-,2-,4-,5-,6-,8-,9- and 10-monophenols. In contrast, UGT1*6 lacked activity towards the dihydrodiols and metabolized a more limited range of monophenols, namely 4-,5-,8- and 12-hydroxyB[a]P. Both UGT2B7 and UGT1*6 glucuronidated N, 1-,3- and 8-hydroxyAAF, but 5-hydroxyAAF was metabolised only by UGT1*6. Neither enzyme glucuronidated 3-,7- and 11-hydroxyB[a]P and 7- and 9-hydroxyAAF, although these compounds were all metabolised by human liver microsomal UGTs. The results suggest that the relative content of UGT isoforms in a cell or tissue will be important for determining the extent to which a particular carcinogen/mutagen is deactivated.
The contrast sensitivity of 51 low vision patients (95 eyes) showed a substantial decrease in all spatial frequencies. The peak contrast sensitivity was shifted to 1 C/D from the normal 3-4 C/D. The high-frequency cut off is correlated to the visual acuity positively. Of the 33 patients, the preferred eye was the eye with better peak sensitivity in 28 patients (84%), while the preferred eye was the eye with better visual acuity in 22 patients (66%). It seems that the peak sensitivity is more important than visual acuity in determining eye preference. It provides a useful information for the clinician to determine which eye to train with low vision aids. Forty patients among 46 patients (87%) with RFN (Recognized Frequency Number) > or = 3 are able to read No.5 reading card, while 5 patients among 5 patients with RFN < 3 are not able to read No.5 reading card. The contributions of CSF to the low vision are evaluated.
Reading rehabilitation was done for 51 low vision patients who underwent tests of the contrast sensitivity function (CSF) and the visual field. The results showed that the recognized frequency of CSF was related to the reading capability. The CSF was useful in predicting the reading prognosis, and visual field impairment significantly affected the reading ability. The relationship between the reading rehabilitation and the visual functions was discussed.
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