Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase

Abstract

Protein-calorie malnutrition (PCM) can develop both from inadequate food intake and as a consequence of diseases such as cancer and AIDS. Several studies have shown that PCM can alter drug clearance but little information is available on the effect of PCM on individual cytochrome P450 isoforms and phase II conjugation enzymes. The aim of the present study was to begin a systematic 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. After 3 weeks, the animals were sacrificed and microsomal and cytosolic fractions prepared. Ethoxyresorufin O-deethylation (EROD), chlorzoxazone 6-hydroxylation, dextromethorphan N- and O-demethylation and 1-chloro-2,4-dinitrobenzene (CDNB) conjugation were used as measures of CYP1A, CYP2E1, CYP3A2, CYP2D1 and glutathione S-transferase (GST) activity, respectively. Additionally, NADPH-cytochrome P450 reductase activity was measured in the liver microsomes. PCM significantly reduced the maximum velocity (Vmax) 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 dextromethorphan N-demethylation were significantly increased in PCM animals, whereas the K(m) values for chlorzoxazone 6-hydroxylation and dextromethorphan O-demethylation were decreased. In contrast, the K(m) value for CDNB conjugation was unchanged. When NADPH-cytochrome P450 reductase activity was compared, a 29% reduction in reductase activity was noted in PCM animals as compared to controls. Thus, it appears that PCM decreases the overall activity of certain phase I and phase II metabolism enzymes in rat liver while exhibiting differential effects on K(m). Furthermore, this reduction in activity may be due in part to diminished activity of cytochrome P450 reductase.

Effects of Protein Calorie Malnutrition on the Pharmacokinetics of Ketamine in Rats

“…4; Table 1), potentially contributing to the increased anesthetic effects of KET in this rat group. Studies illustrating a PCM-related inhibition of P450s in rodents have been previously reported (Fernandez et al, 1996;Zhang et al, 1999). This inhibition includes the rodent counterparts of those reportedly associated with KET N-demethylation in humans (CYP2B, CYP3A, and CYP2C) (Yanagihara et al, 2001;Hijazi and Boulieu, 2002).…”

“…Animal models of PCM have shown reductions in the clearance of doxorubicin (Cusack et al, 1992) and acetaminophen (Jung, 1985), and altered oxidative drug metabolism (Campbell and Hayes, 1974;Fernandez et al, 1996;Walter-Sack and Klotz, 1996;Zhang et al, 1999), conjugation (Zhang et al, 1999), and protein binding (Varma, 1979). PCM induced alterations in drug metabolism and disposition appear to be multifactorial processes (Anderson, 1988;Zhang et al, 1999), and a complete understanding of the effect of nutritional status on drug pharmacokinetics would be highly desirable for effective clinical treatment.…”

Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients

“…[3][4][5][6] Many reports suggest that undernutrition, which is commonly prevalent in developing countries, may lead to changes in the activity of cytochrome P450-dependent mixed function oxidase [7][8][9][10] and it decreases the activities of CYP3A, CYP2C isoform. [11][12][13][14] Several pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzyme of CYP2C9 affect phenytoin kinetics. [15][16][17][18][19] CYP2C9*2 and CYP2C9*3 are the two most common allelic variants that result in significant reduction in the metabolism of PHT.…”

Modulation of Kupffer cells on hepatic drug metabolism

“…The present study offered further support for a relevant role of Kupffer cells through the control of hepatocyte metabolism mediated liver injury. CYP3A contributed significantly to the biotransformation of xenobiotic chemicals such as drugs, and toxic chemicals [22] . GSTs constitute a multigene family of phase II conjugating enzymes broadly distributed phylogenetically.…”