Gastroenterology

Gastroenterology

Volume 117, Issue 1, July 1999, Pages 89-98
Gastroenterology

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

https://doi.org/10.1016/S0016-5085(99)70554-8Get rights and content

Abstract

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.

GASTROENTEROLOGY 1999;117:89-98

Section snippets

Subjects

This study was performed in 10 healthy volunteers (5 men and 5 women). All subjects were between 18 and 65 years of age, received no prescription or over-the-counter medications for the 2 weeks before the study, and had no significant medical problems. Individuals with a history of smoking or regular alcohol use were excluded. The study was approved by the University of Michigan Institutional Review Board. Written informed consent was obtained from all subjects.

Experimental design

Subjects were admitted to the

Results

Ten healthy adult volunteers (5 men and 5 women) participated in this 12-day inpatient study. The mean age of the 10 subjects was 23.4 years (range, 19–41), and mean subject weight was 66.4 kg (range, 44–85). Each subject received an inducer-free “washout” diet for 5 days, followed by a chargrilled meat–enriched diet for 7 days as described in Subjects and Methods.

Discussion

The aim of this study was to determine if a diet enriched with PAH and HA would induce intestinal and hepatic CYP3A, CYP1A, and Pgp levels in healthy volunteers. Despite the confirmed high levels of PAH and HA in the diet (Table 1), we found no evidence for induction of CYP3A enzymes in either liver, small intestine (Figure 1), or colon. Likewise, we found no evidence for induction of Pgp in the intestine (Figure 2) or colon. This finding is somewhat surprising in light of the known

Acknowledgements

The authors thank Cynthia P. Salmon, Lawrence Livermore National Laboratory, for the heterocyclic amine analysis and Che-Han Hsu for assistance in performing the polycyclic aromatic hydrocarbon analyses.

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    Supported by National Institutes of Health grants GM38149-11 (to P.B.W.), GM53095-01 (to K.S.L.), and MO1RR00042 (to University of Michigan General Clinical Research Center).

    ☆☆

    Address requests for reprints to: Paul B. Watkins, M.D., University of Michigan Medical Center, 1500 East Medical Center Drive, 2150 CCGC 0903, Ann Arbor, Michigan 48109. e-mail: [email protected]; fax: (734) 647-9554.

    Heterocyclic amine analysis was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract W-7405-Eng-48, supported by National Cancer Institute agreement YO1CP2-0523-01 and grant CA55861 from the National Cancer Institute.

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