Effects of protein malnutrition on liver cytochrome p450s

Lee, Ping Cheung; Struve, Mark; Bezerra, Jorge A.; Duncan, Burris

doi:10.1016/s0271-5317(97)00157-7

Cited by 8 publications

(6 citation statements)

References 16 publications

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“…Many experimental studies have shown that protein malnutrition reduces the CYPs activity including CYP3A, CYP2C isoform, and so on. [12][13][14] Hence, mild increase in free PHT in undernourished patients with wild genotype of CYP2C9 (G4 group) could be the result of reduction in the CYP2C9 enzymatic activity in addition to PHT's saturable nonlinear elimination.…”

Section: Discussionmentioning

confidence: 99%

“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Ramasamy

Narayan²,

Shewade³

et al. 2010

Therapeutic Drug Monitoring

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The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further subclassified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 ± 0.62 μg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 μg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 ± 0.52 μg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 μg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 μg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ramasamy

Narayan²,

Shewade³

et al. 2010

Therapeutic Drug Monitoring

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“…This substantial effect on CYP3A2 activity is in agreement with previous results in our laboratory in which we observed a marked reduction in CYP3A2-mediated ifosfamide N-dechloroethylation (37) as well as the results of Lee et ai. (18) studying progesterone 6~-hydroxylation. Interestingly, the K m for dextromethorphan O-demethylation (CYP2DI) decreased in PCM animals, similar to that seen with CYP2El.…”

Section: Discussionmentioning

confidence: 99%

“…Using testosterone metabolism as a general screen for differential effects of PCM on cytochrome P450 oxidations, we have shown that the metabolism of most testosterone metabolites is reduced but that some remain unaffected by PCM, suggesting differential effects on various P450 isoforms (17). Finally, Lee et al (18) have recently demonstrated that PCM had no effect on CYPIAI expression, little effect on CYPIA2 and a pronounced effect on CYP3A expression. Furthermore, these authors demonstrated that CYP3A activity was substantially reduced by PCM.…”

Section: Introductionmentioning

confidence: 96%

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

Zhang

Parentau

Greenly

et al. 1999

Eur. J. Drug Metab. Pharmacokinet.

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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.

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“…Protein malnutrition can affect the pathways of acetaminophen metabolism [5][6][7]. Acetaminophen is metabolized by different pathways such as sulfation, glucuronidation, and some isoforms of hepatic microsomal cytochrome P450s, such as CYP1A2 and CYP3A.…”

Section: Introductionmentioning

confidence: 99%

Potential Susceptibility to Liver Dysfunction Induced by a Therapeutic Dose of Acetaminophen in Rats Submitted to Gestational and Lactational Protein Malnutrition

Siqueira¹

2019

Int J Nutr Sci

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We investigated the potential susceptibility to liver dysfunction induced by a therapeutic dose of acetaminophen in rats submitted to gestational and lactational protein malnutrition using an animal model. Wistar rats were submitted to gestational and lactational protein malnutrition (control, 25% casein, and protein malnutrition, 7% casein). On the 10 th (P10) or on the 25 th (P25) a therapeutic dose of acetaminophen (15 mg/Kg, i.p.) was administered and rats were decapitated 6 hours after acetaminophen administration. Albumin content, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) activities were measured in plasma, as well as the Glutathione (GSH) levels and Glutathione S-Transferase (GST) activity in liver. In both age groups, the treatment with acetaminophen decreased albumin levels and increased ALT and AST activities in plasma. It was also observed decreased hepatic GSH levels and increased GST activity just at P10. An acute therapeutic dose of acetaminophen may induce a mild liver dysfunction in protein malnutrition.

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Effects of protein malnutrition on liver cytochrome p450s

Cited by 8 publications

References 16 publications

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

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

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

Potential Susceptibility to Liver Dysfunction Induced by a Therapeutic Dose of Acetaminophen in Rats Submitted to Gestational and Lactational Protein Malnutrition

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