Suppression of rat hepatic cytochrome P450s by protein-calorie malnutrition: Complete or partial restoration by cysteine or methionine supplementation

Pharmacokinetic profiles of therapeutic agents are altered by protein-calor ie malnutrition (PCM). The current study was designed to determine the expr ession of hepatic cytochrome P450s in rats after protein restriction and to investigate its molecular basis. Western blot analysis revealed that rats with protein restriction for 4 weeks exhibited marked suppression in the he patic P450 1A2, 2C11, 2E1, and 3A1/2 levels. Northern blot analysis showed that hepatic P450 1A2, 2C11, and 3A1/2 mRNAs were significantly decreased i n the state of PCM, The P450 2E1 mRNA level was slightly decreased in PCM r ats, suggesting the possibility that expression of P450 2E1 affected by PCM might result from the transcriptional and/or posttranscriptional regulatio n. PCM-induced changes in most P450 expression completely or partially retu rned to control levels by a week of cysteine supplementation. Cysteine also prevented decreases in P450 1A2, 2C11, 2E1, and 3A1/2 mRNA levels by PCM, Methionine was minimally active in restoring the P450 expression. A metabol ic change in hepatic ethoxyresorufin dealkylase activity in PCM rats was co nsistent with the P450 apoprotein and mRNA levels. Although the plasma conc entrations of azosemide, a loop diuretic, primarily metabolized by cytochro me P450 1A, increased in protein-deprived rats, cysteine supplementation si gnificantly reduced the increased plasma concentrations of the drug. The al tered pharmacokinetic parameters of azosemide in PCM rats returned to those of control after cysteine supplementation, corroborating the conclusion th at cysteine was effective in restoring cytochrome P450 expression and metab olic activities. (C) 1999 Academic Press.