UNC General Clinical Research Center

Cytochrome P450 Information for Investigators

Liver oxidative metabolism reflects the activity of several cytochrome P450 enzymes that are located in the liver microsomal fraction. This enzymatic system plays a major role in the metabolism of many compounds including prostaglandin’s, biliary acids, steroids, carcinogens and drugs. Cytochrome P450’s are found in animals, plants and bacteria.

This system is now recognized for participation in drug activation, toxic metabolite production and promotion of the carcinogenic potential of some substances. Different drugs may induce the cytochrome P450 system. By using antipyrine clearance as a marker of oxidative function it has been possible to demonstrate that many other factors may stimulate oxidative metabolism such as diet, physical exercise and surgical procedures with a duration of less than 2 hours. Conditions such as liver disease, aging and surgical procedures with a duration of 2 hours or more will inhibit the system.

The processes of induction and inhibition of the P450 system play an essential role in the levels of drugs that are substrates in the system. This is important regarding efficacy or toxicity of these drugs.

Nutritional status of the subject, diet composition and administration of parenteral formulas can influence oxidative metabolism. Protein deficiency might increase the toxicity of certain drugs. Fasting and vitamin C status also inhibit liver metabolism of several drugs. Different vegetables, such as Brussels sprouts or cabbage induce the metabolism of some carcinogens, phenazetin and hexobarbital in the GI tract of rodents. Further studies on the influence of macronutrients showed that rats fed protein-deficient diets had reduced cytochrome P450 content and cytochrome P450 reductase activity. Lipid composition of the diet can also change the fatty acid composition of the microsomes.

Another interesting thing to note is that switching from a protein-rich diet to a CHO-rich diet can also affect oxidative metabolism. Antipyrine half life is longer on the CHO-rich diet than on the protein-rich one. Many vegetables like Brussels sprouts or cabbage as well as certain forms of broiled meat increase antipyrine clearance in humans. Vitamin C supps also stimulate antipyrine metabolism.

Results in elderly populations have been inconclusive on the above responses to certain foods and macronutrients. The depression of oxidative metabolism in the aged is thought to be an important contributing factor.

In Parenteral nutrition (PN) liver microsomal membranes have shown significant changes in rats fed different types of lipids. These changes were not found to correlate with microsomal enzymatic activity.

In humans, effects of BCAA’s vs. conventional amino acids have shown that antipyrine clearance increased using the conventional solution. This confirms the level of amino acids influence antipyrine metabolism and the effect occurs without changes in the amount of calories received.

As in orally fed subjects, there is a difference in antipyrine clearance in PN solutions administered using more CHO. CHO as the sole caloric source had a lower rate of antipyrine clearance than subjects receiving lipids. Cytochrome P450 activity and lipogenesis are NADPH dependent and it has been demonstrated that CHO-based PN patterns are more lipogenic than lipid-based PN patterns. The competition for NADPH between cytochrome P450 and lipogenesis could be responsible for the results mentioned above. Lipids may improve protein synthesis and reduce liver damage, especially if administered as medium-chain/long-chain mixtures.

Conclusions:

It appears that the relationship between CHO and protein is more important than the total amount of protein ingested, but the biochemical mechanisms for the liver cytochrome P450 responses to high and low protein diets are still unknown.

PUFA’s may modify membrane fluidity and this could affect the function of liver microsomes that are rich in membranes. Changes in lipid components might alter intracellular transport while a lowered membrane fluidity may reduce substrate affinity for the P450 system. However, there are many unknown steps to relate lipids to oxidative metabolism.

There may be other factors involved with metabolism like GI hormones for example. Differences seen in animal studies when looking at PN vs. enteral nutrition suggest responsible factors other than nutrients.

In the mean time, provision of nutrition, not only can modify nutritional status but can also affect changes in the liver. It is important to note that grapefruit juice and red wine can inhibit hepatic and intestinal cytochrome P450 by flavonoids and/or other chemicals.

It is also prudent to advise the restriction of cruciferous vegetables and charbroiled or broiled foods for any studies examining the cytochrome P450 system. The research is too scant to make sound recommendations regarding CHO, protein and fat content for now. There is a file with articles concerning cytochrome P450 and also nutrition and drug metabolism. Feel free to browse through it at any time. We will try to keep it up to date.

References:

Ameer B, Weintraub RA. Drug Interactions with Grapefruit Juice. Clin Pharmacokinet 33: 103-121, 1997.

Chan WK, Nguyen LT, Miller VP, Harriz RZ. Mechanism-Based Inactivation of Human Cytochrome P450 3A4 by Grapefruit Juice and Red Wine. Life Sciences 62: 135-142, 1998. Jorquera F, Culebras JM, Gonzalez-Gallergo J. Nutrition 12: 442-447, 1996. Influence of Nutrition on Liver Oxidative Metabolism. (review)

Edwards DJ, Bellevue FH, Woster PM. Identification of 6',7'-dihydroxybergamottin, a Cytochrome P450 Inhibitor, in Grapefruit Juice. Drug Metabolism and Disposition 24: 1287-1290, 1996.

Fuhr U. Maier A, Keller A, Steinijans VW, Sauter R, Staib AH. Lacking Effect of Grapefruit Juice on Theophylline Pharmacokinetics. International Journal of Clinical Pharmacology and Therpeutics 33: 311-314, 1995.

Fukuda K, Ohta T, Yamazoe Y. Grapefruit Component Interacting with Rat and Human P450 CYP3A: Possible Involvement of Non-Flavonoid Components in Drug Interaction. Biol Pharm Bull 20: 560-564, 1997.

Feldman EB. How Grapefruit Juice Potentiates Drug Bioavailability. Nutr Rev 55: 398-400. (review)

Hollander AA, Rooij J, Lentjes EG, Arbouw F, vanBree JB, Schoemaker RC, vanEs LA, vanderWoude FJ, Cohen AF. the effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther 56: 318-324, 1995.

Kall MA, Clausen J. Dietary effect on mixed function P450 1A2 activity assayed by estimation of caffeine metabolism in man. Hum Exp Toxicol 1995 oct;(10): 801-7.

Kall MA, Vang O, Clausen. Effects of dietary broccoli on human in vivo drug metabolizing enzymes: caffeine, oestrone and chloroxazone metabolism. Carcinogenesis 1996; 17:(4):793-799.

Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guy W, Watkins PB. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. J Clin Invest 99: 2545-2553, 1997.

Walter-Sack I, Klotz U. Influence of Diet and Nutritional Status on Drug Metabolism. Clin Pharmacokinet 31: 47-64, 1996.