Variations in the sugar, organic acid, and amino acid composition of table grape berries were determined in three successive years in 129 grape cultivars. Three regional groups were represented among these cultivars; European, North American, and Japanese. All cultivars are conserved at the Fukuoka Agricultural Research Center in Japan. Three representative ripe average-sized bunches were selected from one vine per cultivar. Ripeness was judged by visual observation of seed color change to dark brown, without senescence of berry tissue. Soluble solids content (SSC) was weakly correlated with other berry traits, but strongly correlated with total sugar content. Genotypic variance (r g 2 ) was significant for all berry traits, especially for a ratio (sugar composition) and c ratio (amino acid composition). The yearly effect (r y 2 ) was significant for SSC, total sugar content, and total amino acid content but not for a ratio, titratable acidity, b ratio (organic acid composition) and c ratio. Repeatabilities over the 3 years were very high for a ratio and c ratio, while they were low for SSC, total sugar content, titratable acidity, b ratio, and amino acid content. Correlation coefficients between the values of each individual year and the 3-year mean were relatively high for the a ratio and c ratio. We highlight the varietal differences in the a ratio and c ratio because of the low environmental variation. Two types of grape were distinguished on the basis of sugar composition: hexose accumulators (a ratio C 0.81) and sucrose accumulators (a ratio B 0.80). The hexose-and sucrose-accumulating traits were related to genetic or regional differences. Cultivars were classified into five types on the basis of the c ratio. Like the a ratio, variation in the c ratio is closely related to cultivar parentage and regional differences. Vitis vinifera cultivars exhibited a skewed distribution with a c ratio below 1.0 because they contain low levels of sweet amino acids. In contrast, the c ratio frequently exceeded 1.5 in American hybrid cultivars because they contain high levels of sweet amino acids.

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39-Hydroxy-49-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces glutathioneconjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. After a single oral administration of diclofenac to humanized mice, the unchanged drug in plasma peaked at 0.25 hour and then declined with a half-life (t 1/2 ) of 2.4 hours. 49-Hydroxydiclofenac (II) and 39-hydroxydiclofenac also peaked at 0.25 hour and were undetectable within 24 hours. However, VI peaked at 8 hours and declined with a t 1/2 of 13 hours. When diclofenac was given once per day, peak and trough levels of VI reached plateau within 3 days. Studies with administration of II suggested VI was generated via II as an intermediate. Among six reported glutathione-conjugated metabolites of diclofenac, M1 (5-hydroxy-4-(glutathion-S-yl)diclofenac) to M6 (29-(glutathion-S-yl)monoclofenac), we found three dichlorinated conjugates [M1, M2 (49-hydroxy-39-(glutathion-S-yl)diclofenac), and M3 (5-hydroxy-6-(glutathion-S-yl)diclofenac)], and a single monochlorinated conjugate [M4 (29-hydroxy-39-(glutathion-S-yl)monoclofenac) or M5 (49-hydroxy-29-(glutathion-S-yl)monoclofenac)], in the bile of humanized chimeric mice. M4 and M5 are positional isomers and have been previously reported as human-specific in vitro metabolites likely generated via arene oxide and quinone imine-type intermediates, respectively. The biliary monochlorinated metabolite exhibited the same mass spectrum as those of M4 and M5, and we discuss whether this conjugate corresponded to M4 or M5. Overall, humanized TK-NOG chimeric mice were considered to be a functional tool for the study of drug metabolism of diclofenac in humans.

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