Activities of Krebs-Henseleit enzymes in normal and cirrhotic human liver.

Abstract

Activities of 5 Krebs-Henseleit (KH) enzymes [carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OT), argininosuccinic acid synthetase (ASS), argininosuccine acid lyase (AS], and arginase (A)] were determined in liver tissue obtained at laparotomy from 17 patients with alcoholic cirrhosis, and from 19 individuals without liver disease. Specific activities of the 5 enzymes were calculated on the basis of 4 units of reference: wet weight, total N, noncollagen N, and DNA. Specific activities of all 5 enzymes were depressed in the cirrhotic liver. Degree of reduction was similar regardless of which unit of reference was employed to calculate specific activity. Average extent of depression for activity per milligram of DNA was 54 per cent, 37 per cent, 50 per cent, 64 per cent, and 69 per cent for CPS, OT, ASS, AS, and A, respectively. Rate-limiting enzymes for operation of KH cycle were CPS, ASS, and AS in both normal and cirrhotic livers. Extent of loss of these three enzymes in cirrhotic liver measured in vitro correlated with reduction in maximal rate of urea synthesis and with severity of NH,CI intolerance measured in vivo. I n cirrhotic patients, plasma concentrations of urea and NH, tend to be below and above normal, respectively. We recently found the maximal rate of urea synthesis (MRIJS) in cirrhotic patients, following ingestion of casein or infusion of free amino acids, was 8 to 89 per cent of this rate in normal subjects.’ Hepatic patients whose MRIJS was less than 20 per cent of normal were usually hyperammonemic. These observations indicated that in cirrhotic patients, the pathway NH, + urea is restricted. Where is the obstruction ? Possibilities include : (1) diminished delivery of substrates (amino acids and NH,) to hepatic enzyme systems because of vascular shunting; (2) reduced activities of one or more hepatic enzymes of the Krebs-Henseleit (KH) cycle [carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (CT), argininosuccinic acid synthetase (ASS), argininosuccinic acid lyase (AS), and arginase (A) ] ; (3) subnormal activity of hepatic glutamine synthetase. To investigate (2) above, we have measured activities of KH enzymes in