Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers.

BACKGROUND & AIMS: Carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons present in chargrilled meat are substrates for inducible CYP1A and CYP3A enzymes and for P-glycoprotein. We examined whether consumption of a chargrilled meat diet results in induction of these proteins. METHODS: Ten healthy adults were fed a diet enriched with chargrilled meat for 7 days. Duodenal biopsy specimens were obtained on days 1, 5, and 12 and analyzed for CYP1A, CYP3A, and P-glycoprotein messenger RNA (mRNA) and protein. On days 5 and 12, hepatic CYP3A4 and CYP1A2 activities were measured and colon biopsies were performed. The levels of polycyclic aromatic hydrocarbon DNA adducts in peripheral blood mononuclear cells were measured on days 1, 4, 11, and 26. RESULTS: There was no detectable induction of CYP3A4, CYP3A5, or P-glycoprotein mRNAs or protein in small intestine or colon and no induction of hepatic CYP3A4 enzyme activity. In contrast, the chargrilled meat diet resulted in unequivocal induction of CYP1A enzymes in the liver and small intestine of each subject. There was an inverse correlation between the level of peripheral polycyclic aromatic hydrocarbon DNA adducts measured on day 11 and both liver CYP1A2 activity (P = 0.027) and enterocyte CYP1A1 protein concentration (P = 0.046). CONCLUSIONS: Ingestion of chargrilled meat results in induction of CYP1A enzymes but not CYP3A4 or P-glycoprotein. This observation, combined with the correlation between adduct levels and CYP1A expression, supports an adaptive role for CYP1A but not CYP3A4 or P-glycoprotein.

Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.

Chronic psychological effects of exercise and exercise plus cognitive strategies.

Psychological changes associated with 16-wk moderate and low intensity exercise training programs, two of which possessed a cognitive component, were evaluated. Subjects were healthy, sedentary adults, 69 women (mean age = 54.8 +/- 8.3 yr) and 66 men (mean age = 50.6 +/- 8.0 yr). Participants were randomly assigned to a control group (C), moderate intensity walking group (MW), low intensity walking group (LW), low intensity walking plus relaxation response group (LWR), or mindful exercise (ME) group-a Tai Chi type program. Women in the ME group experienced reductions in mood disturbance (tension, P < 0.01; depression, P < 0.05; anger, P < 0.008; confusion, P < 0.02; and total mood disturbance, P < 0.006) and an improvement in general mood (P < 0.04). Women in the MW group noted greater satisfaction with physical attributes (body cathexis, P < 0.03), and men in MW reported increased positive affect (P < 0.006). No other differences were observed between groups on measures of mood, self-esteem, personality, or life satisfaction. Equivocal support is provided for the hypothesis that exercise plus cognitive strategy training programs are more effective than exercise programs lacking a structured cognitive component in promoting psychological benefits.