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Laboratório de Bioquímica Nutricional e de Alimentos, Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
2To whom correspondence should be addressed. E-mail: donangel{at}iq.ufrj.br
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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500 mg/d, participated in two tests, caffeine load (5 mg/kg body weight) and no-caffeine control, in a randomized crossover design. The net increase (caffeine load corrected by no caffeine) in urinary excretion of most minerals was significantly higher in -OC than in +OC (P < 0.05), with the larger group difference for calcium (ninefold) followed by magnesium (twofold), zinc (onefold) and potassium (onefold). Net increases in urinary excretion of 1-methylurate and paraxanthine were about three- and fivefold higher, respectively, in -OC than in +OC (P < 0.05) whereas net increases in urinary excretion of 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1,7-dimethylurate were over twofold higher in the +OC than in -OC (P < 0.05). Following the caffeine load, most urinary minerals showed negative correlation with urinary 1-methylurate in -OC (R 
-0.78, P < 0.01), and with urinary AFMU and 1,7-dimethylurate in +OC (R -0.84, P < 0.01). Oral contraceptives appear to limit the renal effect of caffeine on mineral excretion possibly by reducing paraxanthine excretion, the most active caffeine metabolite.
KEY WORDS: • caffeine metabolism • hormonal contraceptives • urinary minerals • calcium • zinc
Caffeine is a nonnutritive bioactive substance widely consumed in many countries in the form of beverages, foods and medications (1
). In addition to its recognized stimulatory effect on the central nervous system, caffeine affects several other tissues and organs, including the kidney, where it increases water and mineral urinary excretion (2
). Acute ingestion of caffeine in amounts such as those found in two to three cups of coffee (300 mg caffeine) increases the urinary excretion of calcium, magnesium and sodium for at least 3 h after consumption (3
–7
). Renal conservation over 24 h after a caffeine load appears insufficient to offset the caffeine-induced calcium and magnesium losses (6
). These increased urinary losses may potentially affect bone mass by increasing bone mineral release to maintain balance (8
). The urinary excretion of zinc may also increase with caffeine intake (9
). Zinc is an essential mineral for bone formation (10
) and almost 30% of total body zinc in the adult is present in bone (11
).
Caffeine consumption has been related to reduced calcium retention (2
,12
), decreased bone mineral density (13
–15
) and increased risk of hip fracture (16
,17
). High caffeine intake is considered a risk factor for osteoporosis, particularly when calcium intake is low (18
,19
). However, many studies have reported no association between caffeine intake and bone or calcium homeostasis (20
–26
). This suggests that there is physiological adaptation to the bone and renal effects of caffeine under conditions not yet clearly identified.
Steroid hormone status appears to influence caffeine use. Reduced caffeine clearance was observed in pregnancy (27
), with use of estrogen replacement therapy (28
) and with use of hormone oral contraceptives (29
,30
). In vitro studies with human liver microsomes have shown that synthetic estrogen inactivates cytochrome P4501A2, a key enzyme involved in caffeine metabolism (31
,32
). Changes of caffeine metabolism in response to steroid hormones may modify its renal effects. The relationship between caffeine-induced urinary mineral excretion and caffeine metabolism has not yet been investigated.
The purpose of this study was to evaluate the effect of use of oral contraceptives on the urinary excretion of calcium, magnesium, phosphorous, zinc, sodium, potassium and caffeine metabolites, and their relationship, in response to an acute caffeine load. The study was conducted in young adult women who habitually consume a low calcium diet.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Thirty women, 20–29 y of age, participated in the study after informed consent. The procedures in the study were according to the Helsinki Declaration as revised in 1983. The women were nonsmokers, apparently healthy, with adequate weight for height, no history of renal, bone or gastrointestinal disorders, no recent use of mineral/vitamin supplements and with dietary calcium intake lower than 1000 mg/d. Fifteen women were users of oral contraceptives (OC)3 (monophasic preparations providing 20–40 µg ethinylestradiol daily combined with a progestagen agent; +OC group). The other 15 women were nonusers of OC (-OC group). Before participation in the study, customary dietary intake of calcium, other minerals and caffeine was assessed by a food frequency questionnaire. Daily intakes were estimated using the program "The Food Processor" (ESHA Research, Salem, OR) with database adapted to Brazilian foods based on published information (33
). The women maintained their dietary habits during the study.
Experimental design.
Each woman participated in two different tests, caffeine load and no caffeine, in a randomized crossover design in which each woman was her own control. The tests were done on different days with a washout period of at least 7 d between the test days. The caffeine load (5 mg/kg body weight) was ingested as coffee beverage (regular instant coffee, 36 mg caffeine/g) and the no-caffeine control consisted of ingestion of decaffeinated instant coffee beverage (<0.4 mg caffeine/g), providing an identical weight of coffee powder. Caffeine load ranged from 245 to 345 mg (mean 285 mg). Before each test, each woman fasted for 10–12 h, emptied her bladder and drank 240 mL of deionized water early in the morning. A fasting urine sample was obtained approximately 1 h later. A fasting blood sample (10 mL) was collected by venous puncture into heparin-containing tubes, before the first test. The coffee beverage of the corresponding test (caffeine load or no caffeine) was immediately ingested together with a light meal consisting of cream crackers (30 g), butter (10 g) and fruit jam (15 g). All the urine produced during the following 4 h was collected into appropriate plastic containers.
Laboratory analysis.
All materials used for sample collection, storage and analysis were either disposable or previously soaked overnight in dilute nitric acid (1:4) and carefully rinsed with deionized water. Plasma samples were obtained by centrifugation of the blood samples immediately after being drawn. The volume of 4-h test urine samples was determined by weight of the total urine and measurement of the urine density. Urine aliquots for determination of creatinine and minerals were acidified with HCl (final concentration 0.01 mol/L) and those for measurement of caffeine metabolites were acidified with ascorbic acid (final concentration 6.7 g/L). Urine (fasting and 4-h test) and plasma aliquots were kept frozen at -20°C until analysis.
Hematocrit was determined by conventional capillary centrifugation. Blood hemoglobin was measured by the cyanomethemoglobin method using a commercial kit (BioClin, Belo Horizonte, Brazil). Calcium in plasma and urine was determined by the methyl thymol blue method; phosphorus in plasma and urine, by the method of Fiske and Subbarow (34
); plasma albumin, with bromocresol green; and creatinine in urine, by the Jaffe reaction, as previously described (35
). Magnesium in plasma and urine was determined by reaction with calmagite using a commercial kit (BioMérieux, Marcy l’Etoile, France). Zinc in plasma and urine was measured by atomic absorption flame spectrometry (Perkin Elmer AA3300; Perkin Elmer Life Sciences, Boston, MA). Sodium and potassium in plasma were determined by flame emission spectrometry (Micronal B26, São Paulo, Brazil).
Caffeine metabolites determined in urine were: 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylurate (1U), 1-methylxanthine (1X), 1,7-dimethylurate (17U) and paraxanthine (17X). These combined metabolites correspond to over 80% of total caffeine metabolites in human urine (32
). Caffeine metabolites in urine were extracted and measured by HPLC as described by Krul and Hageman (36
). Briefly, N-acetaminophen (150 mg/L; Sigma, St. Louis, MO) was added to 200 µL of urine and extracted with chloroform/isopropanol (4:1, v/v). After centrifugation for 5 min at 1000 x g, the organic phase was removed, evaporated under a stream of nitrogen and dissolved in 1 mL of 0.05% acetic acid. A 20-µL aliquot was injected onto an HPLC column (Merck LiChrospher 100 RP-18, 5 µm, 250 x 4.6 mm i.d.) with a mobile phase of acetic acid (33%)/tetrahydrofuran/acetonitrile/water (1:2.5:44:952.5, v/v). The column effluent was monitored at 280 nm (SPD-10AV UV-VIS detector; Shimadzu, Kyoto, Japan). Metabolite standards were from Sigma, except AFMU that was donated by Nestlé Research Center, Lausanne, Switzerland.
Statistical analysis.
Values are means ± SD for normally distributed variables (descriptive characteristics of women, urinary minerals, volume and creatinine), and as median (minimum–maximum) for nonnormally distributed variables (urinary caffeine metabolites). For urinary minerals, responses to caffeine load compared to no caffeine within each group (-OC or +OC) were assessed by paired t-test, with each woman being her own control. Differences by OC use in net increase (caffeine load corrected by no caffeine) in urinary excretions were examined by unpaired t-test. For caffeine metabolites, the Wilcoxon test was used to examine the responses to the caffeine load, with each woman being her own control, and the Mann–Whitney test was used to evaluate the differences by OC use in net increases. The relationship between urinary mineral excretions and caffeine metabolites was examined using the Pearson correlation matrix (minerals vs. minerals), and the Spearman correlation matrix (minerals vs. caffeine metabolites). Values of P < 0.05 were considered significant. The statistical analysis was performed using Statgraphics Version 7 for DOS (Manugistics, Cambridge, MA).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Women in the +OC group had lower (P < 0.05) plasma albumin and calcium concentrations than women in the -OC group. Habitual dietary intakes of calcium, phosphorus and zinc were similar in both groups (Table 2
) but magnesium intake was higher (P < 0.05) in the +OC group. Mean dietary intakes of calcium, magnesium and zinc were 48, 61 and 90%, respectively, of recommended intakes in the United States and Canada for young adult women (37
). The consumption of caffeine was very similar in -OC and +OC, with a median intake of 90 mg/d. The main food sources of caffeine were (in decreasing order) coffee, guaraná and mate.
|
|
). Urinary volume increased (mean 42%) after the caffeine load compared with no caffeine (P < 0.05), both in -OC and in +OC women. Creatinine excretion was not affected significantly by the caffeine load in either group. The urinary excretions of calcium, magnesium and sodium increased onefold or more after the caffeine load compared to no caffeine in the -OC group (P < 0.05) but excretions did not change significantly in the +OC group. Urinary phosphorous was not affected by the caffeine load in either group. Urinary excretion of zinc and potassium increased after the caffeine load compared to no caffeine, both in -OC and +OC (P < 0.05). The increase in urinary zinc excretion after the caffeine load compared with no caffeine was over threefold in -OC and about twofold in +OC. The increase in urinary potassium was over onefold in -OC and less than onefold in +OC.
|
). Net increases in urinary excretion of calcium, magnesium, zinc and potassium were significantly higher in -OC than in +OC women (P < 0.05). The larger difference between groups was observed for calcium (ninefold) followed by magnesium (twofold), zinc (onefold) and potassium (onefold). The net increase in urinary excretion of sodium did not differ between the -OC and +OC groups.
|
). Urinary excretions of 1-methylurate and paraxanthine were significantly increased after the caffeine load compared with no caffeine only in the -OC group (P < 0.05), whereas excretions of AFMU and 1,7-dimethylurate increased only in the +OC group (P < 0.01). The urinary excretion of 1-methylxanthine was not different between the caffeine load and the no-caffeine tests in either group.
|
). Net increases in urinary excretion of 1-methylurate and paraxanthine after the caffeine load were about three- and fivefold higher, respectively, in -OC compared to +OC women (P < 0.05). In contrast, net increases in urinary excretion of AFMU and 1,7-dimethylurate after the caffeine load were over twofold higher in the +OC group compared to the -OC group (P < 0.05).
|
). The pattern of correlations between minerals and caffeine metabolites appeared different in the -OC and +OC groups. In -OC, negative correlations were observed between the urinary excretions of calcium, magnesium, sodium and potassium with the excretion of 1-methylurate (R -0.78, P < 0.01). In contrast, in the +OC group, negative correlations were observed between the urinary excretions of calcium and magnesium with that of AFMU and 1,7-dimethylurate (R -0.92, P < 0.01), and between urinary potassium and 1,7-dimethylurate (R = -0.84, P < 0.01). No significant correlations were found in 4-h urine after the no-caffeine test in either -OC or +OC women.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The women studied were healthy and with normal plasma concentrations of minerals. The users of oral contraceptives had lower plasma calcium and albumin concentrations than nonusers as previously observed (38
). Habitual calcium dietary intake of the women was less than half the recommended intakes for young adult women in the United States and Canada (36
). Low calcium intake, which appears to be common in Brazil (39
,40
), is of concern because it may predispose women to bone loss and osteoporosis (15
,18
) and it may increase the burden of caffeine intake on calcium homeostasis (19
). The habitual caffeine consumption of the women studied (90 mg/d) was low when compared to that of women studied in the United States (>200 mg/d) (15
,20
,21
,41
). The habitually low caffeine consumption of the women in the present study possibly makes them more sensitive to the renal effects of an acute caffeine challenge.
The increased urinary volume after the caffeine load observed in this study was an expected response (4
). The diuretic effect of caffeine has been related to increased renal blood flow, increased glomerular filtration rate and decreased tubular reabsorption of sodium ions (42
). However, the acute caffeine intake did not significantly increase creatinine excretion in 4-h urine, consistent with previous observations in other studies (3
,4
,43
,44
). Therefore, increased glomerular filtration may not be the main mechanism explaining caffeine-induced diuresis. The present study indicates that use of oral hormonal contraceptives does not prevent the diuretic effect of caffeine.
Many studies in adult women show that a caffeine load acutely increases urinary excretion of calcium, magnesium and sodium (3
–7
). A caffeine load also increased urinary potassium (4
) but not urinary phosphorous (5
,45
). None of these studies was controlled for oral contraceptive use. In the present study, we observed increased urinary excretion of minerals (and significant correlations between minerals) in response to the caffeine load mainly in the women nonusers of oral contraceptives. Calcium and magnesium excretions increased significantly only in these women, whereas zinc and potassium excretion increased significantly in all women, although to a lower extent in those using hormonal contraceptives. Therefore, the use of oral contraceptive appeared to blunt the effect of caffeine on urinary mineral excretion. This blunting effect was particularly strong for urinary calcium, with a reduction in the acute net response to caffeine by a factor of about 10. These results suggest that the renal handling of minerals in response to caffeine intake is modified with the use of hormonal contraceptives, which is consistent with studies showing that oral contraceptives can reduce the urinary loss of calcium (38
) and zinc (46
).
The effect of caffeine intake on urinary zinc was previously reported in healthy males (9
). In the present study, urinary zinc excretion increased after the caffeine load in all women, independent of oral contraceptive use. In the women nonusers of oral contraceptives, urinary zinc increased relatively more than urinary calcium after the caffeine load compared to no caffeine (over threefold for zinc, and over onefold for calcium), suggesting that the renal handling of zinc is very sensitive to caffeine. Caffeine intake may affect zinc balance in women with low zinc intakes and this possibility merits further investigation.
The renal effects of caffeine have been explained by stimulation of renal prostaglandin synthesis and by antagonism to endogenous adenosine for adenosine receptors (7
,42
). The active substances appear to be caffeine and especially its metabolite paraxanthine (42
,47
). An in vitro study showed that paraxanthine has higher affinity for the adenosine receptor than caffeine, whereas other caffeine metabolites do not bind to the receptor (47
). Studies in women have shown that synthetic estrogens decrease the plasma paraxanthine/caffeine ratio as well as caffeine clearance, independent of the coadministered progestogen (28
–30
). Therefore, it is possible that use of hormone contraceptives modifies caffeine metabolism, as indicated in the present study by the urinary caffeine metabolites measured in response to the caffeine challenge.
Measurement of urinary metabolites is a well-established, noninvasive method to investigate caffeine metabolism (32
,48
,49
). The formation of paraxanthine, by N3-demethylation catalyzed by cytochrome P4501A2, accounts for 80% of caffeine metabolism in humans (49
). Once formed, paraxanthine undergoes N7-demethylation catalyzed also by cytochrome P4501A2 to form 1-methylxanthine, which is the main pathway, but it can also be 8-hydroxylated by cytochrome P4502A6 to form 1,7-dimethylurate, or it can be acetylated by N-acetyltransferase2 to form AFMU. Further oxidation of 1-methylxanthine by xanthine oxidase forms 1-methylurate (49
). Urinary 1-methylurate and 1-methylxanthine account for 43% of caffeine metabolites normally excreted in humans, whereas urinary AFMU and 1,7-dimethylurate usually account for <20% (42
). Measurement of major urinary metabolites is useful to evaluate any possible interference on caffeine metabolism such as that caused by oral contraceptive use.
In the present study, the pattern of increase in urinary caffeine metabolites after the caffeine load was different in the women users and nonusers of oral contraceptives. The metabolites with larger increases in the -OC women were paraxanthine and 1-methylurate, corresponding to the main pathway of caffeine metabolism. In contrast, in the +OC women, the metabolites excreted more after the caffeine load were those of the branching pathways, AFMU and 1,7-dimethylurate, possibly as a consequence of inhibition of liver cytochrome P4501A2 by ethinylestradiol (28
,31
,32
). In the women not using oral contraceptives, the net increase in urinary paraxanthine excretion after the caffeine load was about fivefold that of nonusers, which probably makes them more sensitive to the renal effects of caffeine that are mainly attributable to the formation of paraxanthine (42
,47
).
The physiological effects of caffeine metabolites other than paraxanthine are not known but results from this study suggest an indirect protective role of 1-methylurate, AFMU and 1,7-dimethylurate on renal mineral conservation. After the caffeine load, an inverse correlation was seen between urinary concentrations of calcium, magnesium, sodium and potassium with that of 1-methylurate in the -OC women and with those of AFMU and 1,7-dimethylurate in the +OC women. Increased production of 1-methylurate, AFMU and 1,7-dimethylurate may indicate a more extensive paraxanthine metabolism, thus reducing its physiological actions.
In conclusion, our study demonstrates that use of hormone oral contraceptives blunts the acute increase in urinary excretion of calcium, magnesium and, to a lower extent, of zinc and potassium, induced by caffeine in young adult women. Oral contraceptives appear to influence the metabolism of caffeine, reducing paraxanthine urinary excretion and possibly limiting its physiological effects. These findings are particularly relevant for women with low calcium intake who need to preserve body minerals essential for bone health.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AFMU, 5-acetylamino-6-formylamino-3-methyluracil; 17U, 1,7-dimethylxanthine; 1U, 1-methylurate; 1X, 1-methylxanthine; OC, oral contraceptive; 17X, paraxanthine.
Manuscript received 12 September 2002. Initial review completed 1 October 2002. Revision accepted 25 October 2002.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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; -OC, 
. Different from corresponding value in -OC group, a, P < 0.05; b, P < 0.01 (unpaired t-test).