腎実質内における酵素,NAGおよびγ-GTPの局在からみたCDDP腎障害

Abstract

CDDP 5日間連続投与患者の尿中NAGおよびγ-GTP活性を同時に測定して, その急性変動様式の比較から尿細管障害の発生機序について検討した.1) CDDP投与によりNAGおよびγ-GTPの尿中排泄は増加し, CDDP投与中(Day 3)にγ-GTPは第1のピークを示し, 投与終了日ないし直後(Day 5, 6)にNAGのピーク及びγ-GTPの第2のピークをみた.2) CDDP投与早期にγ-GTPの尿中活性が増加することから, まずγ-GTPを多く含む刷子縁が障害され, つぎにライソゾームを含む細胞実質の障害が起っていると考えられる.3) CDDPが尿細管上皮細胞に達する経路としては, 尿細管管腔側からのものの他に毛細血管から基底膜を通して移行する経路が考えられるが, CDDPによる腎障害には虚血性変化による障害の存在も考えられる.4) γ-GTPに二相性の活性上昇パターンをみたことから, 刷子縁に含まれるγ-GTPとは細胞内局在部位の異なるγ-GTPが存在する可能性がある

Nephrotoxicity is the major side effect of CDDP and it develops renal tubular damage. In the present paper, we have studied acute effects of cis-dichlorodiamine platinum (CDDP, 20 mg daily for 5 days) on the renal tubule using urinary NAG and gamma-glutamyltranspeptidase (gamma-GTP) activities as indicators of the toxicity. Altogether 25 courses of chemotherapy in 15 patients who had malignant tumors were studied. Urinary enzyme activities consisting of N-acetyl-beta-D-glucosaminidase (NAG, lysosomal enzyme) and gamma-GTP (brush border enzyme) were measured for 11 days from the day before CDDP administration. In all cases, both urinary enzyme activities increased with CDDP administration. The increase of NAG activity was transient; the highest level was detected on the 5th day of chemotherapy and decreased after that. On the other hand, two peaks of gamma-GTP activity were observed in many cases, the first peak during chemotherapy and the second peak soon after the completion of CDDP administration. The differences in increase pattern of these two urinary enzyme activities, suggest that changes of brush border occur in an early stage and cellular tissue including lysosome of renal tubule is impaired afterwards.