Journal of Nutrition Animal Diets/Enrichment Products...

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blank, R.
Right arrow Articles by Wolffram, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blank, R.
Right arrow Articles by Wolffram, S.
© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2355-2358, September 2004

Nutrient Interactions and Toxicity

Alkalinization of Urinary pH Accelerates Renal Excretion of Ochratoxin A in Pigs1

Ralf Blank2 and Siegfried Wolffram

Institute of Animal Nutrition, Physiology, and Metabolism, Christian-Albrechts-University Kiel, 24098 Kiel, Germany

2To whom correspondence should be addressed. E-mail: blank{at}aninut.uni-kiel.de.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
The mycotoxin ochratoxin A (OA) is a cause of endemic nephropathy in farm animals and humans. Reabsorption of OA along the nephron results from nonionic diffusion and by carrier-mediated mechanisms, indicating that urine alkalinization may help to accelerate OA excretion and thus reduce its toxicity. The aim of the present study was to investigate the effect of a dietary sodium bicarbonate supplementation as a means of increasing urinary pH on the systemic availability and excretion of OA in pigs. Dietary supplementation of 2% sodium bicarbonate significantly increased urinary pH (5.7 ± 0.2 to 8.3 ± 0.1) and daily urine volume (1108 ± 276 to 2479 ± 912 mL). The systemic availability of OA and its dechloro-analog, Ochratoxin B (OB), calculated as the area under the curve (AUC) was reduced to 75 and 68%, respectively, of the control group (P < 0.05). This effect was due mainly to an accelerated elimination of OA and OB in the urine. The faster renal elimination may be due to reduced reabsorption of the ochratoxins by nonionic diffusion, and other H+-dependent mechanisms. Thus, urinary alkalinization may be an efficient means to partially reduce the toxic effects of OA in pigs.

KEY WORDS: • bioavailability • excretion • mycotoxins • ochratoxin A • ochratoxin B

The worldwide occurrence of ochratoxin A (OA)3 contamination of raw agricultural products has been amply documented; it occurs in a variety of plant products such as cereals, coffee beans, and dried fruits (1–3). The average contamination level of feedstuffs is in the range of 0.1–0.5 mg/kg but can be >5 mg/kg under unfavorable storage conditions (1). Furthermore, contamination of animal products such as pigs’ kidney, blood sausages, meat, and milk occurs as a result of feeding animals OA-contaminated feed (3–6). With respect to the carryover of OA to humans, animal products derived from monogastric species such as pigs are of greater relevance than those derived from ruminants (7).

Due to striking similarities between the porcine nephropathy caused by OA and the Balkan Endemic Nephropathy including the development of urinary tract tumors in humans (8), OA is assumed to be a causative agent in the development of the human disease as well, although other risk factors may be involved (9). The International Agency for Research on Cancer (IARC) classified OA as a putative human carcinogen (10). Because of the ubiquitous occurrence of OA in improperly stored food and feedstuffs, there is a high risk of exposure for humans and animals. Effective methods are required in animal production either to detoxify OA-containing feedstuffs or to reduce its absorption and/or to enhance its elimination from the body.

According to previous studies (11), OA is subjected to extensive reabsorption along the nephron, resulting in an accumulation of OA in the kidney. This is of toxicologic importance because renal reabsorption contributes to the long half-life of the mycotoxin in the body. From microinfusion and microperfusion studies in rats (12), it was concluded that reabsorption of OA along the nephron results mainly from nonionic diffusion and in a minor way from other carrier-mediated mechanisms (H+-dipeptide cotransporter, organic anion transporter). These findings indicate that urine alkalinization may accelerate renal OA excretion and thus reduce its toxicity. Thus, the present study investigated the effect of urine alkalinization by means of dietary sodium bicarbonate (NaHCO3) supplementation on the systemic availability and excretion of OA in pigs and its dechloro-analog ochratoxin B (OB), which often occurs with OA in contaminated feedstuffs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Chemicals. Ochratoxin A, OB, O{alpha}, and Oß were produced from inoculated wheat as previously described (13,14). All other chemicals were derived from the following sources: chloroform, 2-propanol (Mallinckrodt Baker), magnesium chloride (Sigma-Aldrich), hydrochloric acid (Merck), methanol, and ortho-phosophoric acid (Roth).

    Animals. Castrated male pigs (n = 7; cross-breed, German Hybrid Pig Breeding Programme) surgically equipped with a permanent jugular vein catheter (Cook Deutschland) and a mean body weight of 36.7 ± 2.0 kg were used. Twice each day, the pigs were restrictively fed (1400 g/d) a commercially available pig diet4 (Fa. Plambeck) based on barley, wheat, soybean meal, and corn. During the study, pigs were kept in metabolism crates with free access to tap water.

    Treatment groups and diets. Control pigs (n = 3) were fed the commercially available standard diet. The treated group (NaHCO3, n = 4) received the same diet except that it contained 2% NaHCO3. The dietary electrolyte balance (dEB, Na + K –Cl) of the control and NaHCO3 diets were 170 and 400 mEq/kg diet.

Throughout d 3 and 4 of the feeding period, urinary pH was monitored several times. On d 5, the pigs received a single portion of 150 g of wheat containing 6.0 µmol OA, 1.0 µmol OB, 0.12 µmol ochratoxin {alpha} (O{alpha}), and 0.45 µmol ochratoxin ß (Oß). After exposure to OA, jugular blood samples were collected for 96 h. Urine and feces were collected each day for 4 d and stored frozen until analysis. The total daily urine volume was recorded before OA exposure to differentiate between effects of NaHCO3 and OA on daily urine volume because both NaHCO3 and OA may induce polyuria (15,16). Animal care and experimental procedures were conducted according to the German Guidelines and Regulations on Animal Care (Deutsches Tierschutzgesetz 1986, Durchführung von Tierversuchen).

    Analytical procedures. Serum samples prepared from blood were stored at –20°C until analysis. Feces were freeze-dried and ground through a 0.2-mm screen before analysis. Urine was thawed and an aliquot of 10 mL was taken for analysis. Extraction of ochratoxins from blood serum, feces, and urine and analysis by HPLC were performed as described previously (17).

    Statistical analysis. Data are presented as means ± SD. Bartlett’s test for homogeneity of variances revealed that variances for all data among groups were equal. Serum concentrations, water intake, urine volume, as well as daily fecal and urinary excretion of the ochratoxins, were subjected to repeated-measures analysis using the MIXED procedure of SAS vers. 6.12 (SAS Institute). A spatial covariance structure was used, which assumes a reduction in correlation in relation to the power of the distance between time points. The model included treatment, time, and their interaction. The LSMEANS follow-up test was used for comparison of means. Urinary pH, growth performance, total fecal and urinary excretion of the ochratoxins and the area under the curve (AUC) of the concentration-time profiles of OA and OB in serum, calculated according to the trapezoidal rule, were analyzed using the General Linear Model procedure. The Tukey-Kramer test was used for comparison of means. Differences were considered significant when P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Growth performance of the pigs was unaffected by treatment. Daily body weight gain and feed conversion efficiency were 620 ± 65 g/d and 0.44 ± 0.05 kg gain/kg feed for the control group and 518 ± 108 g/d and 0.36 ± 0.07 for the NaHCO3 group, respectively. Supplementation of NaHCO3 increased (P < 0.05) the urinary pH from 5.7 ± 0.2 to 8.3 ± 0.1. This was accompanied by an increase (P < 0.05) in daily urine volume from 1108 ± 276 to 2479 ± 912 mL compared with the control group. Daily urine volume was not affected by time, indicating that in both groups, OA exposure did not induce polyuria. Water consumption tended to be greater (P = 0.16) in the NaHCO3 (2078 ± 597 mL/d) than in the control group (1697 ± 456 mL/d). Urine output was higher than water intake in the NaHCO3 group, indicating dehydration of pigs administered NaHCO3. However, these results should not be overemphasized for the following reasons. First, water consumption could not be corrected for water spillage. Second, the number of observations is rather low and there were considerable interindividual differences in urine output (range: 505–4320 mL/d). Furthermore, it seems possible that the water and diet intakes of pigs were not fully synchronized, due to the relatively short adaptation time.

Due to clogging of the jugular vein catheter in 2 pigs after administration of OA, the serum concentrations of control and the NaHCO3 group are derived only from 2 and 3 pigs, respectively. The serum appearance/disappearance curves of OA and OB (Fig. 1) revealed that both mycotoxins were rapidly absorbed within 5–8 h after ingestion. The maximum serum concentrations for OA and OB were obtained between 7 and 8 h and 5 and 7 h, respectively, after ingestion of contaminated wheat (Table 1). After 12 h, serum concentrations of OA and OB were significantly lower in the NaHCO3-treated group (Fig. 1). The relative bioavailability of the mycotoxins, calculated as the AUC (control = 100%), was reduced (P < 0.05) by 25% for OA and 33% for OB due to NaHCO3 treatment.



View larger version (18K):
[in this window]
[in a new window]
  		FIGURE 1 Serum appearance/disappearance curves of ochratoxin A (upper panel) and ochratoxin B (lower panel) in pigs fed a diet containing 2% NaHCO3 (n = 2) or a control diet (n = 3). Values are means ± SD. * Different from NaHCO3, P < 0.05

 

View this table:
[in this window]
[in a new window]
  		TABLE 1 Toxicokinetic parameters of ochratoxin A and ochratoxin B in pigs fed a diet containing 2% NaHCO3 or a control diet1

 
Daily excretion of OA in urine was 1- to 2-fold higher (P < 0.05) in the NaHCO3 group compared with the control group, resulting in a total urinary excretion of 0.99 ± 0.25 and 0.33 ± 0.14 µmol for the NaHCO3 and the control group, respectively. The concentration of OA in urine, however, was not affected by treatment or time (data not shown). Total excretion of OB in urine was also significantly higher in the NaHCO3 group (0.60 ± 0.16 µmol) compared with the control group (0.26 ± 0.05 µmol) due to a much higher excretion of OB on d 1 after ingestion. Excretion of OB decreased with time and only minor amounts were excreted on d 3–4 after exposure, consistent with the nearly complete disappearance of OB from serum within 3 d after exposure.

Ochratoxin {alpha} and Oß are formed by microbial hydrolytic cleavage of the phenylalanine group of OA and OB, respectively. Urinary excretion of O{alpha} in the NaHCO3 group was greater than in controls on d 1 after exposure, leading to an increased total excretion (0.34 ± 0.06 vs. 0.23 ± 0.02 µmol). Urinary excretion of Oß was not affected by NaHCO3. Total excretion of OA, O{alpha}, and Oß in feces was not affected by treatment but decreased with time, whereas fecal excretion of OB was significantly reduced by the NaHCO3 treatment (data not shown). This might be explained by a more pronounced renal elimination, which in turn might result in lower biliary secretion of OB.

Intact OA was excreted mainly in the urine and was 2 times higher in the NaHCO3 group than in the control group (Table 2). The low proportional urinary excretion of O{alpha}, which is derived mainly from OA, indicates that neither postabsorptive generation nor intestinal absorption of O{alpha} from the large intestine is of major importance. In addition, the high fecal excretion of O{alpha} indicates that microbial hydrolysis of nonabsorbed OA in the large intestine was nearly complete. Total fecal recovery of OA and O{alpha} in feces was in the range of 40–45% of the ingested dose, indicating that the intestinal absorption of OA is 50–60% of an oral dose. For OB, total urinary and fecal excretion (OB + Oß) was 42% higher than intake (Table 2), because contaminated wheat also contained additional 0.12 µmol O{alpha} (2.1% of the total OA dose) and 0.45 µmol Oß (45% of the OB dose). Consequently, the total intake of OB and Oß was excreted within 4 d in the NaHCO3 group, whereas in the control group, excretion of OB and Oß was ~69% of the total ingested OB and Oß. Because fecal excretion of Oß was similar in both groups, the missing fraction in the control group may have been due to conversion of OB or Oß to other metabolites during liver passage (conjugation, methylation, and hydroxylation), which were not analyzed.


View this table:
[in this window]
[in a new window]
  		TABLE 2 Proportional urinary and fecal excretion of ochratoxin A, ochratoxin B, and their corresponding metabolites, ochratoxin {alpha} and ochratoxin ß, in pigs fed a diet containing 2% NaHCO3 or a control diet1

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
As a weak acid (pKa = 7.1), OA is predominantly absorbed by nonionic diffusion along the gastrointestinal tract (18), with the proximal jejunum as the site of maximal absorption (19). In blood, >99% of OA is bound to plasma albumin (20). This not only facilitates passive absorption of the nonionized form but also delays elimination of OA because filtration in the kidney is hindered. In addition, OA undergoes enterohepatic circulation (21) as well as reabsorption along the nephron (11,12), increasing the exposure time and accumulation of OA in liver and kidneys. Reducing the reentrance of OA into the systemic circulation should accelerate the elimination of OA with a concomitant reduction in its toxicity. Reabsorption of OA in the kidney results in part from nonionic diffusion (12). Urinary alkalinization increases the renal excretion of weak acids because increasing pH increases the ionized form, which cannot diffuse across the membrane (22). The aim of this study was to quantify the effect of urinary alkalinization on blood levels and on renal and intestinal excretion of OA. Sodium bicarbonate was used as a urinary alkalinizing agent.

Because the groups did not differ in the serum concentrations of OA and OB during the first 12 h after feeding, absorption of ochratoxins from the gastrointestinal tract appears not to be affected by NaHCO3 treatment. This is consistent with the finding that the supplementation of 2.6% NaHCO3 to the diet of pigs did not affect the pH of gastrointestinal contents (16).

In the present study, fecal excretion of OA and O{alpha} was not affected by NaHCO3 supplementation. In both groups, mainly O{alpha} and only very small amounts of OA were excreted with the feces. Hydrolysis of OA seems to occur mainly in the large intestine and cecum, indicating that the microbial population in the lower portion of the gastrointestinal tract is responsible for the hydrolysis (23). In the present study, fecal excretion of OA and O{alpha} was ~45% of the dose fed, indicating an apparent absorption of OA of ~55%, which is in good agreement with previous results obtained in rats, mice, pigs, and monkeys (24).

Renal elimination of OA contributes up to 50% to its total clearance (25). Carrier-mediated transport of OA by organic anion exchangers located in the basolateral membrane of epithelial cells lining the proximal tubulus is the major pathway for renal secretion of OA (26). According to microperfusion studies in rats (12), ~40% of the reabsorption of OA along the nephron results from nonionic diffusion, 25% is mediated by pH-dependent H+-dipeptide cotransporter, and a further 25% is mediated by the pH-independent apical organic anion transporter OAT-K1. In the present study, renal elimination of OA increased 2-fold after NaHCO3 treatment. Because OA is a weak acid with a pKa value of 7.1, >90% of the OA exists in its ionized form at a urinary pH of 8 (obtained by NaHCO3 treatment in the present study) and thus cannot be reabsorbed passively. The increased sodium intake from NaHCO3 increased the urine volume. A sodium-induced diuresis would be another possible explanation for the enhanced renal elimination of OA. Previous studies in mice, comparing the effect of NaHCO3 vs. ammonium chloride on OA toxicity, showed that NaHCO3 reduced mortality and the number of renal lesions by 20%, whereas ammonium chloride, which leads to urinary acidification and diuresis, did not have any beneficial effect (27). This implies that alkalinization of urine is the main mechanism for the increased elimination of OA. This conclusion is further substantiated by the fact that renal elimination of OA is due mainly to volume-insensitive transcellular secretion along the nephron rather than to filtration in the glomeruli (11,12). The bioavailability and excretion pattern of OB followed the same pattern as OA, indicating that excretion of OB is affected in the same way as OA by NaHCO3 supplementation. Changes in urinary pH can be calculated from dEB (28), which might be useful as a feedstuff-related tool to estimate urinary OA excretion under practical farm situations.

In conclusion, urinary alkalinization by means of 2% NaHCO3 supplementation to pig diets accelerates the urinary excretion of OA by inhibiting the pH-dependent tubular reabsorption, thereby reducing its systemic toxicity. In addition, local toxicity of OA may be influenced by tubular pH as indicated by a reduced activation of caspase-3 and DNA ladder formation in Madin Darby canine kidney cells (MDCK-C7) at a slightly basic extracellular pH compared with slightly acidic conditions (29).


   FOOTNOTES
 
1 Presented in part at the 58th Conference of the Society of Nutrition Physiology, March, 9–11, 2004, Göttingen, Germany [Blank, R. & Wolffram, S. (2004) Effect of dietary sodium bicarbonate supplementation on the toxicokinetics of ochratoxin A and B in pigs. Proc. Soc. Nutr. Physiol. 13: 74]. Back

3 Abbreviations used; AUC, area under the curve; dEB, dietary electrolyte balance; OA, ochratoxin A; O{alpha}, ochratoxion {alpha}; OB, ochratoxin B; Oß, ochratoxin ß. Back

4 Proximate composition of the standard diet (per kg diet): 174 g crude protein, 35 g crude fat, 40 g crude fiber, 13.5 MJ metabolizable energy, 880 g dry matter. Macro mineral and vitamin composition (per kg diet): calcium, 7.8 g; phosphorus, 5.6 g; sodium, 1.9 g; potassium, 8.2 g; chloride, 4.3 g; Mg 1.5 g; retinyl acetate, 58 mg; cholecalciferol, 80 mg; {alpha}-tocopheryl acetate, 80 mg. Back

Manuscript received 31 March 2004. Initial review completed 29 April 2004. Revision accepted 11 June 2004.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

1. Kuiper-Goodman, T. & Scott, P. M. (1989) Risk assessment of the mycotoxin ochratoxin A. Biomed. Environ. Sci. 2:179-248.[Medline]

2. Studer-Rohr, I., Dietrich, D. R., Schlatter, J. & Schlatter, C. (1995) The occurrence of ochratoxin A in coffee. Food Chem. Toxicol. 33:341-355.[Medline]

3. MacDonald, S., Wilson, P., Barnes, K., Damant, A., Massey, R., Mortby, E. & Shepherd, M. J. (1999) Ochratoxin A in dried vine fruit: method development and survey. Food Addit. Contam. 16:253-260.[Medline]

4. Gareis, M. & Scheuer, R. (2000) Ochratoxin A in meat and meat products. Arch. Lebensmittelhyg. 51:102-104.

5. Breitholtz-Emanuelsson, A., Olsen, M., Oskarsson, A., Palminger, I. & Hult, K. (1993) Ochratoxin A in cow’s milk and in human milk with corresponding human blood samples. J. Assoc. Off. Anal. Chem. Int. 76:842-846.

6. Skaug, M. A. (1999) Analysis of Norwegian milk and infant formulas for ochratoxin A. Food Addit. Contam. 26:75-78.

7. Blank, R. (2002) Contribution of animal products to human dietary mycotoxin intake. Z. Umweltchem. Ökotox. 14:104-109.

8. Krogh, P. (1992) Role of ochratoxin A in disease causation. Food. Chem. Toxicol. 30:213-224.[Medline]

9. Tatu, C. A., Orem, W. H., Finkelman, R. B. & Feder, G. L. (1998) The etiology of Balkan Endemic Nephropathy: still more questions than answers. Environ. Health Perspect. 106:689-700.

10. IARC (1993) IARC Monographs on evaluation of carcinogenic risks to humans. Some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins 56:489-521.

11. Zingerle, M., Silbernagl, S. & Gekle, M. (1997) Reabsorption of the nephrotoxin ochratoxin A along the rat nephron in vivo. J. Pharmacol. Exp. Ther. 280:220-224.[Abstract/Free Full Text]

12. Dahlmann, A., Dantzler, W. H., Silbernagl, S. & Gekle, M. (1998) Detailed mapping of ochratoxin A reabsorption along the rat nephron in vivo: the nephrotoxin can be reabsorbed in all nephron segments by different mechanisms. J. Pharmacol. Exp. Ther. 286:157-162.[Abstract/Free Full Text]

13. Xiao, H., Marquardt, R. R., Frohlich, A. A. & Ling, Y. Z. (1995) Synthesis and structural elucidation of analogs of ochratoxin A. J. Agric. Food Chem. 43:524-530.

14. Xiao, H., Marquardt, R. R., Abramson, D. & Frohlich, A. A. (1996) Metabolites of ochratoxins in rat urine and in a culture of Aspergillus ochraceus. Appl. Environm. Microbiol. 62:648-655.[Abstract]

15. Tapia, M. O. & Seawright, A. A. (1984) Experimental ochratoxicosis A in pigs. Austr. Vet. J. 61:219-222.

16. Patience, J. F., Austic, R. E. & Boyd, R. D. (1986) The effect of sodium bicarbonate on acid-base status and protein and energy digestibility in swine. Nutr. Res. 6:263-273.

17. Blank, R., Rolfs, J.-P., Südekum, K.-H., Frohlich, A. A., Marquardt, R. R. & Wolffram, S. (2003) Effects of chronic ingestion of ochratoxin A on blood levels and excretion of the mycotoxin in sheep. J. Agric. Food Chem. 51:6899-6905.[Medline]

18. Kumagai, S. (1988) Effects of plasma ochratoxin A and luminal pH on the jejunal absorption of ochratoxin A in rats. Food Chem. Toxicol. 26:753-758.[Medline]

19. Kumagai, S. & Aibara, K. (1982) Intestinal absorption and secretion of ochratoxin A in the rat. Toxicol. Appl. Pharmacol. 64:94-102.[Medline]

20. Hagelberg, S., Hult, K. & Fuchs, R. (1989) Toxicokinetics of ochratoxin A in several species and its plasma-binding properties. J. Appl. Toxicol. 9:91-96.[Medline]

21. Roth, A., Chakor, K., Creppy, E. E., Kane, A., Röschenthaler, R. & Dirheimer, G. (1988) Evidence for an enterohepatic circulation of ochratoxin A in mice. Toxicology 48:293-308.[Medline]

22. Rang, H. P., Dale, M. M., Ritter, J. M. & Moore, P. K. (2003) Pharmacology 5th ed. 2003 Churchill Livingstone Edinburgh, UK.

23. Madhyastha, M. S., Marquardt, R. R. & Frohlich, A. A. (1992) Hydrolysis of ochratoxin A by the microbial activity of digesta in the gastrointestinal tract of rats. Arch. Environ. Contam. Toxicol. 23:468-472.[Medline]

24. Galtier, P. (1991) Pharmacokinetics of ochratoxin A in animals. Castegnaro, M. Plestina, R. Dirheimer, G. Chernozemsky, I. N. Bartsch, H. eds. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumors 1991:187-200 International Agency for Research on Cancer Lyon, France. .

25. Li, S., Marquardt, R. R., Frohlich, A. A., Vitti, T. G. & Crow, G. (1997) Pharmacokinetics of ochratoxin A and its metabolites in rats. Toxicol. Appl. Pharmacol. 145:82-90.[Medline]

26. Gekle, M. & Silbernagl, S. (1994) The role of the proximal tubule in ochratoxin A nephrotoxicity in vivo: toxodynamic and toxokinetic aspects. Renal Physiol. Biochem. 17:40-49.[Medline]

27. Yong, S., Albassam, M. & Prior, M. (1987) Protective effects of sodium bicarbonate on murine ochratoxicosis. J. Environ. Sci. Health B 22:455-470.[Medline]

28. Patience, J. F. (1990) A review of the role of acid-base balance in amino acid nutrition. J. Anim. Sci. 68:398-408.[Abstract]

29. Schwerdt, G., Freudinger, R., Schuster, C., Silbernagl, S. & Gekle, M. (2003) Inhibition of mitochondria and extracellular acidification enhance ochratoxin A-induced apoptosis in renal collecting duct-derived MDCK-C7 cells. Cell. Physiol. Biochem. 14:47-56.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blank, R.
Right arrow Articles by Wolffram, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blank, R.
Right arrow Articles by Wolffram, S.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]