Forbidden fruit

18 downloads 132 Views 616KB Size Report
megadoses of vitamin C have any major benefits. For example, it has minimal ef- fects in the common cold7, notwithstand- ing the claims of the double Nobel.
© 2001 Nature Publishing Group http://medicine.nature.com

NEWS & VIEWS

10.

11.

© 2001 Nature Publishing Group http://medicine.nature.com

12.

13.

and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82, 743–752 (1995). Chang, W.J. et al. Neuronal nitric oxide synthase and dystrophin-deficient muscular dystrophy. Proc. Natl. Acad. Sci. USA 93, 9142–9147 (1996). Crosbie, R.H. et al. mdx muscle pathology is independent of nNOS perturbation. Hum. Mol. Genet. 7, 823–829 (1998). Thomas, G.D., Hansen, J. & Victor, R.G. ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle. J. Clin. Invest. 99, 2602–2609 (1997). Tidball, J.G. et al. Mechanical loading regulates NOS

14.

15.

16.

17.

expression and activity in developing and adult skeletal muscle. Am. J. Physiol. 275, C260–266 (1998). Lau, K.S. et al. nNOS and eNOS modulate cGMP formation and vascular response in contracting fasttwitch skeletal muscle. Physiol. Genomics 2, 21–27 (2000). Lau, K.S. et al. Skeletal muscle contractions stimulate cGMP formation and attenuate vascular smooth muscle myosin phosphorylation via nitric oxide. FEBS Lett. 431, 71–74 (1998). Duclos, F. et al. Progressive muscular dystrophy in αsarcoglycan deficient mice. J. Cell Biol. 142, 1461–1471 (1998). Durbeej, M. et al. Disruption of the β-sarcoglycan gene

reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol. Cell 5, 141–151 (2000). 18. Coral-Vazquez, R. et al. Disruption of the sarcoglycansarcospan complex in vascular smooth muscle: A novel mechanism for cardiomyopathy and muscular dystrophy. Cell 98, 465–474 (1999).

Department of Physiological Science, University of California, Los Angeles, CA 90095 email: [email protected]

Forbidden fruit Although citrus fruits prevent and cure scurvy, they may not always be as good for you as you thought.

C

itrus fruits have received a good press ever since it was recognized that they can prevent and treat scurvy—first reported by Richard Mead in ‘A Discourse on the Scurvy’ in 1749. This ability to prevent scurvy was later demonstrated in a clinical trial by James Lind, published in 1753 in ‘A Treatise of the Scurvy’. However, it took the British Navy 42 years to recognize the true import of these findings and to implement a preventive strategy on board ship1. But just how good for you are citrus fruits? They contain many substances, the most important being vitamin C (or ascorbic acid), and they certainly prevent and cure vitamin C deficiency—the cause of scurvy. Oranges and lemons, limes and grapefruit contain about 50 mg per 100 g of fruit, although they are topped by strawberries (60 mg per 100 g), members of the Brassica family, such as cabbage and broccoli (50–100 mg per 100 g), green chilli peppers (130 mg per 100 g), black currants (140 mg per 100 g) and parsley, which weighs in at an astonishing 170 mg per 100 g. On the other hand, there is little vitamin C in meat and virtually none in nuts and unfortified cereals. There is some debate about what the recommended daily allowance (RDA) of vitamin C should be. The average daily dose required to prevent scurvy is 46 mg (ref. 2), and the US RDA is 60 mg (ref. 3), although others have suggested that it should be as high as 120 mg (ref. 2) or even 200 mg (ref. 4). However, you can probably meet the daily requirement with an ordinary portion of potatoes (30 mg per 100 g), provided you don’t boil it all away, without needing to eat an orange or a bowl of fortified breakfast cereal. In other words, none of us is likely to run short, and today scurvy is rare enough, even in elderly people, to warrant the publication of individual case reports. But whether excess doses of vitamin C,

J. K. ARONSON by virtue of its antioxidant properties, are beneficial is debatable. These days the consumption of vitamin C is widespread: one

Citrus fruits can be good for you, but can also have drug interactions.

US survey revealed that 40% of the adult population takes a vitamin/mineral supplement, and in 91% of cases the supplement contains vitamin C (ref. 5). This is because vitamin C has been claimed to be of value in a wide range of disorders6, including the common cold, asthma, cancers, coronary artery disease, hypertension, macular degeneration, cataracts and ageing. The fact that all these disorders are unrelated warrants suspicion, and despite many trials there is no conclusive evidence that megadoses of vitamin C have any major benefits. For example, it has minimal effects in the common cold7, notwithstanding the claims of the double Nobel prize-winning guru, Linus Pauling. Antioxidant vitamins are ineffective in preventing macular degeneration8 and the evi-

NATURE MEDICINE • VOLUME 7 • NUMBER 1 • JANUARY 2001

dence that vitamin C has effects in asthma patients is so far contradictory and unimpressive9. This lack of efficacy is not surprising, however, because pharmacokinetic analysis shows that there is no justification for the use of megadoses of ascorbic acid10. The problem is that the body goes to great lengths to avoid excess accumulation of vitamin C, and has at least three ways of accomplishing this. First, absorption of vitamin C from the gut is highly saturable, ensuring that the amount that is absorbed reaches a maximum at relatively low doses. Second, the kidney rapidly excretes vitamin C, because its re-absorption from the renal tubules after filtration by the renal glomerulus is also highly saturable. Virtually all the vitamin C that is absorbed from the gut is thus excreted in the urine. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14 mmol) the mean steady-state plasma concentration increases only from about 12 to 15 mg/l (from 68 to 85 µmol/l)—no matter how high a dose of vitamin C you take orally there is a limit to the plasma concentration that can be reached. Third, tissue uptake is also saturable. An increase in plasma concentration of vitamin C is not associated with a parallel increase in tissue concentration11. Indeed, the tissue vitamin C concentration, measured in leukocytes, saturates at 100 mg daily4 or plasma concentrations of 14 mg/l (80 µmol/l)(ref. 11). So no matter how much you take, all you do is increase the concentrations in your urine and gut, and that can cause adverse effects12. Vitamin C is partly excreted as oxalate, and very high doses can lead to hyperoxaluria and kidney stones13, particularly after intravenous use and in people with renal insufficiency. Adverse effects in the gut include nausea, abdominal cramps and diarrhea14. Moreover, citrus fruits contain many substances other than vitamin C, and some of 29

NEWS & VIEWS

© 2001 Nature Publishing Group http://medicine.nature.com

blinding agent (to disguise the taste of the medication) in a study of the interaction beDrug(s) Effect of grapefruit juice tween felodipine (a calcium Amiodarone Risk of amiodarone toxicity channel blocking agent used (e.g. cardia arrhythmias) to treat hypertension) and alAntihistamines Prolongation of QTc interval; cohol19. Researchers observed (astemizole, terfenadine) risk of ventricular tachycardia that plasma concentrations of Cyclosporin Risk of cyclosporin toxicity felodipine increased when (immunosuppression) the drug was taken with Benzodiazepines Increased drowsiness; grapefruit juice, and this find(alprazolam, diazepam, altered psychometric tests ing was later extended to triazolam, midazolam) other calcium channel blockCalcium channel blockers Reduced blood pressure, ers. Elderly people may be (felodipine, increased heart rate, headaches, particularly susceptible to this nifedipine, nisoldipine) flushing, light-headedness interaction20. Similarly, conLovastatin Risk of lovastatin toxicity current administration of (including rhabdomyolysis grapefruit juice with sedative and renal insufficiency) benzodiazepines alters perforQuinidine Prolongation of QTc interval; mance on psychometric tests risk of ventricular tachycardia and causes increased drowsiSaquinavir Risk of saquinavir toxicity ness21. Sertraline Risk of sertraline toxicity No one knows which of the (serotonin syndrome) chemical entities in grapefruit them, such as grapefruits and Seville or- juice and Seville oranges is responsible for anges, can be dangerous if you’re taking cer- these interactions, although the furatain medications (Table 1). Various isoforms nocoumarins 6’,7’-dihydroxybergamottin of the enzyme cytochrome P450 are respon- and bergamottin, as well as the flavonoids sible for the oxidative metabolism of many naringin and naringenin, seem to have drugs15. One of the isoforms of P450, been exonerated22,23. However, other furaCYP3A4, is found in the gut wall, nocoumarins may be responsible24, and and it metabolizes drugs such since there are hundreds of compounds in as the immunosuppressant cyclo- these fruits25–27 there is much research to be sporin, the calcium channel blockers done. Recent evidence also suggests that felodipine, nifedipine, and nisoldipine, and grapefruit juice inhibits the P-glycoprotein the antihistamine terfenadine. Since that is responsible for the intestinal secreCYP3A4 is responsible for the metabolism of tion of many drugs28, and therefore other these drugs while they are being absorbed drug interactions are to be expected. after oral administration, inhibition of the So it seems that there is a good reason enzyme by something in citrus fruits allows why citrus fruits, particularly the shadthe drugs to escape presystemic metabolism dock, Citrus decumana, were once called and enter the circulation unchanged, poten- “forbidden fruit”. “When the oranges are tially leading to drug toxicity. golden,” runs an old Japanese proverb, This is so important that in some coun- “physicians’ faces grow pale.” And so, it tries a drug label has been introduced, seems, may those of their patients. alerting patients to potential drug interactions with grapefruit: “Do not take grape- 1. Tröhler, U. in To improve the evidence of medicine: The 18th century British origins of a critical approach. (Royal fruit or grapefruit juice while being treated College of Physicians of Edinburgh, Edinburgh) 68–81 16 (United Kingdom, 2000). with this medicine” . In the UK in 1997, Carr, A.C. & Frei, B. Toward a new recommended dithe antihistamine terfenadine was with- 2. etary allowance for vitamin C based on antioxidant drawn from over-the-counter sales because and health effects in humans. Am. J. Clin. Nutr. 69, 1086–1107 (1999). of fears that it caused a life-threatening car3. National Research Council in Recommended dietary aldiac arrhythmia engagingly called “torsade lowances. 10th edn (National Academic Press, de pointes”. This is a form of ventricular Washington DC, 1989). tachycardia, which can occur as a result of 4. Levine, M. et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended diterfenadine toxicity if its metabolism is inetary allowance. Proc. Natl. Acad. Sci. USA 93, 17 3704–3709 (1996). hibited by grapefruit juice . A year later anStewart, M.L., McDonald, J.T., Levy, A.S., Schucker, other antihistamine, astemizole, was 5. R.E. & Henderson, D.P. Vitamin/mineral supplement withdrawn for similar reasons18. use: a telephone survey of adults in the United States. J. Am. Diet. Assoc. 85, 1585–1590 (1985). The ability of grapefruit juice to inhibit 6. Gershoff, S.N. Vitamin C (ascorbic acid): new roles, the metabolism of some drugs was accidennew requirements? Nutr. Rev. 51, 313–326 (1993). tally discovered when it was used as a 7. Douglas, R.M., Chalker, E.B. & Treacy, B. Vitamin C for

© 2001 Nature Publishing Group http://medicine.nature.com

Table 1. Some drug-grapefruit juice interactions

30

8.

9.

10.

11.

12.

13.

14. 15.

16. 17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

preventing and treating the common cold (Cochrane review) in The Cochrane Library. Update Software, Issue 3 (Oxford, UK, 2000). Evans, J.R. & Henshaw, K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration (Cochrane review) in The Cochrane Library. Update Software, Issue 3 (Oxford, UK, 2000). Kaur, B. Vitamin C supplementation asthma (protocol for a Cochrane review) in The Cochrane Library. Update Software, Issue 3 (Oxford, UK, 2000). Blanchard, J., Tozer, T.N. & Rowland, M. Pharmacokinetic perspectives on megadoses of ascorbic acid. Am. J. Clin. Nutr. 66, 1165–1171 (1997). Basu, T.K. & Schorah, C.J. in Vitamin C in health and disease. (The Avi Publishing Company, Westport, Connecticut, 1982). 61–63. Meyers, D.G., Maloley, P.A. & Weeks, D. Safety of antioxidant vitamins. Arch. Intern. Med. 156, 925–935 (1996). Auer, B.L., Auer, D. & Rodgers, A.L. The effect of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin. Chem. Lab. Med. 36, 143–147 (1998). Barness, L.A. Safety considerations with high ascorbic acid dosage. Ann. NY Acad. Sci. 258, 523–528 (1975). Dresser, G.K., Spence, J.D. & Bailey, D.G. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome p450 3A4 inhibition. Clin. Pharmacokinet. 38, 41-57 (2000). Anonymous. Grapefruit warning label: now official in some countries. Drugs Ther. Perspect. 12, 12–13 (1998). Committee on Safety of Medicines, Medicines Control Agency. Terfenadine: now only available on prescription. Curr. Probl. Pharmacovig. 23, 9 (1997). Committee on Safety of Medicines, Medicines Control Agency. Astemizole (Hismanal): only available on prescription. Curr. Probl. Pharmacovig. 25, 2 (1999). Bailey, D.G., Spence, J.D., Edgar, B., Bayliff, C.D. & Arnold, J.M. Ethanol enhances the hemodynamic effects of felodipine. Clin. Invest. Med. 12, 357–362 (1989). Dresser, G.K., Bailey, D.G. & Carruthers, S.G. Grapefruit juice–felodipine interaction in the elderly. Clin. Pharmacol. Ther. 68, 28–34 (2000). Dresser, G.K., Spence, J.D. & Bailey, D.G. Pharmacokinetic–pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin. Pharmacokinet. 38, 41–57 (2000). Bailey, D.G., Malcolm, J., Arnold, O. & Spence, J.D. Grapefruit juice–drug interactions. Br. J. Clin. Pharmacol. 46, 101–110 (1998). Eagling, V.A., Profit, L. & Back, D.J. Inhibition of the CYP3A4-mediated metabolism and P-glycoproteinmediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br. J. Clin. Pharmacol. 48, 543–552 (1999). Guo, L.Q., Fukuda, K., Ohta, T. & Yamazoe, Y. Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Drug Metab. Dispos. 28, 766–771 (2000). Ranganna, S., Govindarajan, V.S. & Ramana, K.V. Citrus fruits—varieties, chemistry, technology, and quality evaluation. Part II. Chemistry, technology, and quality evaluation. Crit. Rev. Food. Sci. Nutr. 18, 313–386 (1983). Ranganna, S., Govindarajan, V.S. & Ramana, K.V. Citrus fruits. Part II. Chemistry, technology, and quality evaluation. B. Technology. Crit. Rev. Food Sci. Nutr. 19, 1–98 (1983). Shaw, P.E., Moshonas, M.G., Hearn, C.J. & Goodner, K.L. Volatile constituents in fresh and processed juices from grapefruit and new grapefruit hybrids. J. Agric. Food Chem. 48, 2425–2429 (2000). Ohnishi, A. et al. Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. Br. J. Pharmacol. 130, 1369–1377 (2000).

University Department of Clinical Pharmacology Radcliffe Infirmary Woodstock Rd. Oxford OX2 6HE, UK

NATURE MEDICINE • VOLUME 7 • NUMBER 1 • JANUARY 2001