Effect of protein-calorie malnutrition on cytochromes P450 and glutathioneS-transferase

Protein-calorie malnutrition (PCM) can develop both from inadequate food in take and as a consequence of diseases such as cancer and AIDS. Several stud ies have shown that PCM can alter drug clearance but little information is available on the effect of PCM on individual cytochrome P450 isoforms and p hase II conjugation enzymes. The aim of the present study was to begin a sy stematic evaluation of the effect of PCM on the activity of individual drug metabolizing enzymes in a rat model of PCM. Control and PCM rats received isocaloric diets which contained either 21% or 5% (deficient) protein. Afte r 3 weeks, the animals were sacrificed and microsomal and cytosolic fractio ns prepared. Ethoxyresorufin O-deethylation (EROD), chlorzoxazone 6-hydroxy lation, dextromethorphan N- and O-demethylation and 1-chloro-2,4-dinitroben zene (CDNB) conjugation were used as measures of CYP1A, CYP2E1, CYP3A2, CYP 2D1 and glutathione S-transferase (GST) activity, respectively. Additionall y, NADPH-cytochrome P450 reductase activity was measured in the liver micro somes. PCM significantly reduced the maximum velocity (V-max) of all model reactions studied. However, differential effects were observed with respect to K-m values of the reactions. The K-m values for EROD and dextromethorph an N-demethylation were significantly increased in PCM animals, whereas the K-m values for chlorzoxazone 6-hydroxylation and dextromethorphan O-demeth ylation were decreased. In contrast, the K-m value for CDNB conjugation was unchanged. When NADPH-cytochrome P450 reductase activity was compared, a 2 9% reduction in reductase activity was noted in PCM animals as compared to controls. Thus, it appears that PCM decreases the overall activity of certa in phase I and phase II metabolism enzymes in rat liver while exhibiting di fferential effects on K-m. Furthermore, this reduction in activity may be d ue in part to diminished activity of cytochrome P450 reductase.