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PABA

Nutrient Name: PABA (para-aminobenzoic acid).
Synonyms: Para-amino benzoic acid, p-aminobenzoic acid, pABA; Potaba. Related Substance: Para-aminobenzoate.

physiology and function

Physiology and Function

Para-aminobenzoic acid (PABA) is a member of the vitamin-B complex but is not generally recognized as an official vitamin.

nutrient in clinical practice

Possible Uses

Arthritis, dermatitis herpetiformis, dermatomyositis, hair graying, infertility (female), insomnia, pemphigus, Peyronie's disease, scleroderma, sunscreen (topical UV obstruction), vitiligo.

Deficiency Symptoms

None established.

Dietary Sources

Whole grains and foods of animal origin, particularly brewer's yeast, wheat germ, bran, and liver.

Nutrient Preparations Available

As a single-ingredient over-the-counter nutraceutical, PABA is usually 100 to 500 mg per dose. More often, small amounts of PABA may be contained within multivitamin or B-complex formulations. Potaba, the potassium salt of PABA, is available by prescription.

Dosage Forms Available

Capsule, tablet.

Dosage Range

Dietary: None established.

Supplemental/Maintenance: Dietary requirement not established.

Pharmacological/Therapeutic: Dosage in clinical trial has ranged from 300 mg to 12 g per day.

Toxic: Toxicity possible with greater than 400 mg PABA; extended use of several grams daily is more likely the range necessary to induce adverse symptoms.

safety profile

Overview

PABA is generally considered to be safe and free of adverse effects at doses up to 400 mg, but minor adverse effects have been reported at doses as low as 30 mg/day. Some symptoms may be attributable to its mildly acidic nature when taken orally; these generally do not occur with the potassium salt of PABA (Potaba). Most reports of significant adverse effects, such as vitiligo or elevated liver enzymes, have been associated with daily doses of 8 to 12 g daily. ^1,2Deaths have been reported at 20 g/day in children and as high as 48 g/day (for 6 days, followed by 7 months at 8 g/day). ^3,4

Nutrient Adverse Effects

Dermatitis, fever, hypoglycemia, itching, liver toxicity, loss of appetite, nausea, vomiting.

Contraindications

Individuals taking sulfonamides and sulfones.

interactions review

Strategic Considerations

Increased PABA levels, resulting from increased endogenous production or increased exogenous (nutraceutical) sources, can cause increased resistance to sulfa drugs (sulfonamides and sulfones) through its effect on folic acid pathways. Patients receiving long-term sulfa drugs (e.g., HIV/AIDS patients on sulfa prophylaxis for Pneumocystis ) are at risk for folic acid deficiencies; for example, megaloblastic anemia is a possible complication. Homocysteine levels often rise with ordinary courses of sulfa antibiotics.

nutrient-drug interactions

Sulfonamides, Sulfones, and Related Sulfa Antibiotics

Evidence: Dapsone (DDS, diaminodiphenylsulphone; Aczone Gel, Avlosulfon), sulfasalazine (salazosulfapyridine, salicylazosulfapyridine, suphasalazine; Apo-Sulfasalazine, Azulfidine, Azulfidine EN-Tabs, PMS-Sulfasalazine, Salazopyrin, Salazopyrin EN-Tabs, SAS); combination drug: sulfamethoxazole and trimethoprim (cotrimoxazole, co-trimoxazole, SXT, TMP-SMX, TMP-sulfa; Bactrim, Bactrim DS, Cotrim, Septra, Septra DS, Sulfatrim, Uroplus); sulfamethoxazole (Gantanol). Extrapolated, based on similar properties: Sodium sulfacetamide (AK-Sulf, Bleph-10, Sodium Sulamyd), sulfanilamide (AVC), sulfisoxazole (Gantrisin), triple sulfa (Sultrin Triple Sulfa).

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate

Probability: 2. Probable
Evidence Base:

Consensus

Effect and Mechanism of Action

Sulfones and sulfonamides exert their antimicrobial action by competitively displacing para-aminobenzoic acid (PABA) from its binding site on 7,8-dihydropteroate synthase (DHPS), an enzyme critical for de novo synthesis of folic acid by many pathogenic microorganisms. Specifically, DHPS catalyzes the condensation of PABA with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. Consequently, sulfonamide and sulfone drugs cause cell death by depleting the folate pool necessary to microbial growth. Furthermore, extended use of sulfa drugs can result in depletion of PABA as well as depletion of folate and subsequent elevation of homocysteine. Conscientious physicians are advised to coadminister folic acid when they prescribe sulfa drugs.

Research

The phenomenon of sulfonamide-resistant infections was first discussed in the late 1960s, but the mechanism of action underlying the effectiveness of sulfa drugs only gradually became known, with increasing knowledge of the interaction between PABA and this important class of antibiotics.

In a 1966 clinical trial involving 39 volunteers subjected to mosquito-borne malaria infections, Degowin et al. ⁵ observed that PABA intake impaired the antimalarial activity of dapsone (DDS) against chloroquine-resistant Plasmodium falciparum. The five subjects receiving both PABA (1 g four times daily) and dapsone (25 mg daily) demonstrated acute malaria, in contrast to subjects given dapsone only, before and for 1 month after exposure, in whom malaria was suppressed. Irshaid et al. ⁶ (1993) found that PABA substantially inhibited the acetylation of dapsone (DDS) by whole blood taken from both slow and rapid acetylators. In 1994, McConkey et al. ⁷ showed that auxotrophs of P. falciparumwere dependent on p-aminobenzoic acid for growth. That same year, Voeller et al. ⁸ described the interaction of Pneumocystis cariniiDHPS with sulfonamides and diaminodiphenyl sulfone (dapsone) and clarified that DHPS is the target enzyme for the sulfonamide compounds. In a subsequent study of the pharmacokinetic parameters of elimination of sulfamoyl benzoic acids, sulfonamides, and penicillins via tubular secretion, Ehlert et al. ⁹ observed inhibition of the conjugation of PABA with glycine in vitro.

In a 1999 paper, Vinnicombe and Derrick ¹⁰ investigated the enzymatic mechanism and sulfonamide inhibition of DHPS from the pathogen Streptococcus pneumoniae. Using equilibrium binding assays, they showed that binding of the substrate PABA to DHPS was absolutely dependent on the presence of pyrophosphate, which acts as an analog of the second substrate 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP), and that the product of the reaction, dihydropteroate, was also able to bind to DHPS. Sulfonamides were capable of displacing PABA in a competitive manner. Thus, the authors determined that the specific target for sulfonamide inhibition of S. pneumoniaeDHPS is the enzyme-DHPPP binary complex. Shortly thereafter, in an experiment using Saccharomyces cerevisiae, Castelli et al. ¹¹ found that 15 sulfa drugs inhibited yeast growth in a manner indicating competition with PABA. Such competition resulted from direct addition of PABA or through increased expression of the PABA synthase gene.

Despite the axiomatic mechanism involved and the consistent evidence available in the interaction, its incidence and severity remain largely unclear.

Clinical Implications and Adaptations

Physicians prescribing sulfa drugs should advise patients to refrain from concomitant use of PABA, to avoid interference with the therapeutic activity of the medication. Although there is no known and agreed therapeutic ceiling for PABA dosing that would not interfere with sulfa therapy, daily doses greater than 100 mg twice daily are more likely to have a clinically significant effect. Whether it is also necessary to avoid B-complex or multivitamin formulas containing lower levels of PABA remains uncertain.

Further clinical research is warranted to determine the clinical significance of various dosage levels of pABA intake in relation to particular sulfa agents and respective pathogens, as well as the importance and implications of folate coadministration for patients undergoing long-term treatment with sulfones and sulfonamide antibiotics.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Chemotherapy and Radiation, Particularly Paclitaxel

Evidence: Paclitaxel (Paxene, Taxol).

Following reports that PABA might be capable of inhibiting the development of melanoma in vitro, Dr. Peter Brooks ¹² and colleagues at New York University School of Medicine conducted research on highly melanotic B16F10 melanoma cells, as well as lung and breast carcinoma cells, using PABA alone and in conjunction with conventional cancer therapies. PABA alone had little effect on proliferation, but these researchers observed substantial inhibition of proliferation if the cells were treated with PABA and then treated with ionizing radiation and/or chemotherapy. Subsequent experiments with melanoma-bearing mice yielded similar results. In particular, a significant decrease in tumor progression was noted in tumors treated with PABA plus paclitaxel (Taxol) and/or ionizing radiation, compared with tumors left untreated or treated with paclitaxel alone. Although the mechanism of PABA action remains unknown, results of differential complementary DNA (cDNA) array analysis suggest that PABA upregulates cell cycle control genes and downregulates DNA repair enzymes. Such preliminary findings suggest a possible role for PABA in optimizing existing cancer therapies. These researchers have begun a clinical trial investigating concomitant administration of paclitaxel and PABA in the treatment of patients with melanoma.

Methotrexate

Methotrexate (Folex, Maxtrex, Rheumatrex).

As a dihydrofolate reductase (DHFR) inhibitor, methotrexate interferes with folic acid activation while PABA increases folate availability through its effect on DHPS. Consequently, PABA coadministration, or folic acid intake, has been found to interfere with the therapeutic activity of methotrexate in individuals being treated for cancer. ¹³ However, the action of methotrexate in the treatment of rheumatoid arthritis or psoriasis does not depend on folate suppression, so administration of PABA (as well as folic acid or folinic acid) is not contraindicated, even though it might lower methotrexate levels, and can be beneficial in reducing adverse effects associated with the drug. ^14-21 Close supervision and regular monitoring are appropriate during any such coadministration. Further research into such concomitant therapeutic protocols is warranted.

Citations and Reference Literature

1.Hughes CG. Oral PABA and vitiligo. J Am Acad Dermatol 1983;9:770.View Abstract
2.Kantor GR, Ratz JL. Liver toxicity from potassium para-aminobenzoate. J Am Acad Dermatol 1985;13:671-672.View Abstract
3.Zarafonetis CJD, Grekin RH, Curtis AC et al. Further studies on the treatment of lupus erythematosus with sodium para-aminobenzoate. J Invest Dermatol 1948;11:359.
4.Worobec S, LaChine A. Dangers of orally administered para-aminobenzoic acid. JAMA 1984;251:2348.View Abstract
5.Degowin RL, Eppes RB, Carson PE et al. The effects of diaphenylsulfone (DDS) against chloroquine-resistant Plasmodium falciparum. Bull World Health Organ 1966;34:671-681. View Abstract
6.Irshaid YM, al-Hadidi HF, Abuirjeie MA et al. Acetylation of dapsone by human whole blood. Int J Clin Pharmacol Ther Toxicol 1993;31:18-22.View Abstract
7.McConkey GA, Ittarat I, Meshnick SR, McCutchan TF. Auxotrophs of Plasmodium falciparum dependent on p-aminobenzoic acid for growth. Proc Natl Acad Sci USA 1994;91:4244-4248.View Abstract
8.Voeller D, Kovacs J, Andrawis V et al. Interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (dapsone). J Infect Dis 1994;169:456-459.View Abstract
9.Ehlert C, Strunz H, Visser K et al. Inhibition of the conjugation of PABA with glycine in vitro by sulfamoyl benzoic acids, sulfonamides, and penicillins and its relation to tubular secretion. J Pharm Sci 1998;87:785.View Abstract
10.Vinnicombe HG, Derrick JP. Dihydropteroate synthase from Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition. Biochem Biophys Res Commun 1999;258:752-757.View Abstract
11.Castelli LA, Nguyen NP, Macreadie IG. Sulfa drug screening in yeast: fifteen sulfa drugs compete with p-aminobenzoate in Saccharomyces cerevisiae. FEMS Microbiol Lett 2001;199:181-184.View Abstract
12.Brooks P. In vitro and in vivo radiosensitization by p-aminobenzoic acid (PABA): Abstract 1005. International Conference on Molecular Targets and Cancer Therapeutics. New York; 2003.
13.Antineoplastics, antimetabolites, methotrexate. In: Threlkeld DS, ed. Facts and Comparisons Drug Information. St Louis: Facts and Comparisons; 1990:653-654.
14.Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol 1984;26:121-124.View Abstract
15.Morgan SL, Baggott JE, Vaughn WH et al. 5 mg or 50 mg/week dose of folic acid supplementation does not alter the efficacy of methotrexate treated rheumatoid arthritis patients (abstract). Arthritis Rheum 1993;36:S79.
16.Morgan S, Alarcon GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. J Rheumatol 1993;20:929-930.
17.Shiroky JB, Neville C, Esdaile JM et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis: results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1993;36:795-803.View Abstract
18.Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol 1993;28:466-469.View Abstract
19.Morgan SL, Baggott JE, Vaughn WH et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-841.
20.Ortiz Z, Shea B, Suarez-Almazor ME et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: a metaanalysis of randomized controlled trials. J Rheumatol 1998;25:36-43.View Abstract
21.Bressolle F, Kinowski JM, Morel J et al. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol 2000;27:2110-2114.View Abstract
.[No authors listed.] Drug evaluations subscription. Vol. 2. Section 13. Chicago: American Association; 1993.
.[No authors listed.] Physicians’ desk reference. Montvale, NJ: Medical Economics Co, Inc; 2003.
.Baca AM, Sirawaraporn R, Turley S, et al. Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action. J Mol Biol 2000;302(5):1193-1212.
.Birdsall B, Burgen AS, Roberts GC. Effects of coenzyme analogues on the binding of p-aminobenzoyl-L-glutamate and 2,4-diaminopyrimidine to Lactobacillus casei dihydrofolate reductase. Biochemistry 1980;19(16):3732-3737.
.Cannon WR, Garrison BJ, Benkovic SJ. Consideration of the pH-dependent inhibition of dihydrofolate reductase by methotrexate. J Mol Biol 1997;271(4):656-668.
.Carson CC. Potassium para-aminobenzoate for the treatment of Peyronie’s disease: is it effective? Tech Urol 1997;3:135-139.
.Castelli LA, Nguyen NP, Macreadie IG. Sulfa drug screening in yeast: fifteen sulfa drugs compete with p-aminobenzoate in Saccharomyces cerevisiae. FEMS Microbiol Lett 2001;199(2):181-184.
.Clegg DO, Reading JC, Mayes MD. Comparison of aminobenzoate potassium and placebo in the treatment of scleroderma. J Rheumatol 1994;21:105-110.
.Ehlert C, Strunz H, Visser K, et al. Inhibition of the conjugation of PABA with glycine in vitro by sulfamoyl benzoic acids, sulfonamides, and penicillins and its relation to tubular secretion. J Pharm Sci 1998;87(1):101-108.
.Fan H, Brunham RC, McClarty G. Acquisition and synthesis of folates by obligate intracellular bacteria of the genus Chlamydia. J Clin Invest 1992;90(5):1803-1811.
.Gaby AR. The story of PABA. Nutr Healing 1997; 3-4,11. (Review)
.Grace WJ, Kennedy RJ, Formato A. Therapy of scleroderma and dermatomyositis. N Y State J Med 1963;63:140-144.
.Hasche-Klunder R. Treatment of Peyronie’s disease with para-aminobenzoacidic potassium (Potoba). Urologe [A] 1978;17:224-247.
.Holt GA. Food and drug interactions. Chicago: Precept Press; 1998:170.
.Hughes CG. Oral PABA and vitiligo. J Am Acad Dermatol 1983;9:770. (Letter)
.Hyde JE, Sims PF. Sulfa-drug resistance in Plasmodium falciparum. Trends Parasitol 2001;17(6):265-256.
.Irshaid YM, al-Hadidi HF, Abuirjeie MA, et al. Acetylation of dapsone by human whole blood. Int J Clin Pharmacol Ther Toxicol 1993;31(1):18-22.
.Kantor GR, Ratz JL. Liver toxicity from potassium para-aminobenzoate. J Am Acad Dermatol 1985;13:671-672. (Letter)
.Ludwig G. Evaluation of conservative therapeutic approaches to Peyronie’s disease (fibrotic induration of the penis). Urol Int 1991;47:236-239.
.McConkey GA, Ittarat I, Meshnick SR, et al. Auxotrophs of Plasmodium falciparum dependent on p-aminobenzoic acid for growth. Proc Natl Acad Sci U S A 1994;91(10):4244-4248.
.Rosowsky A, Wright JE, Vaidya CM, et al. The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L- ornithine. Pharmacol Ther 2000;85(3):191-205.
.Sieve BF. Further investigations in the treatment of vitiligo. Virginia Med Monthly 1945:6-17.
.Sieve BF. The clinical effects of a new B-complex factor, para-aminobenzoic acid, on pigmentation and fertility. South Med Surg 1942;104:135-139.
.Then RL. Mechanisms of resistance to trimethoprim, the sulfonamides, and trimethoprim-sulfamethoxazole. Rev Infect Dis 1982;4(2):261-269. (Review)
.Voeller D, Kovacs J, Andrawis V, et al. Interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (dapsone). J Infect Dis 1994;169(2):456-459.
.Voice RA, Manis M, Weber WW. Inhibition of human red blood cell N-acetyltransferase. Drug Metab Dispos 1993;21(1):181-183.
.Wiesel LL, Barritt AS, Stumpe WM. The synergistic action of para-aminobenzoic acid and cortisone in the treatment of rheumatoid arthritis. Am J Med Sci 1951;222:243-248.
.Willis I, Kligman AM. Aminobenzoic acid and its esters: the quest for more effective sunscreens. Arch Dermatol 1970;102:405-417.
.Worobec S, LaChine A. Dangers of orally administered para-aminobenzoic acid. JAMA 1984;251:2348.
.Zarafonetis CJD, Curtis AC, Shaw JM. Treatment of pemphigus with potassium para-aminobenzoate. Am J Med Sci 1956;231:30-50.
.Zarafonetis CJ, Dabich L, Devol EB, et al. Retrospective studies in scleroderma: pulmonary findings and effect of potassium p-aminobenzoate on vital capacity. Respiration 1989;56:22-33.
.Zarafonetis CJD, Dabich L, Negri D, et al. Retrospective studies in scleroderma: effect of potassium para-aminobenzoate on survival. J Clin Epidemiol 1988;41:193-205.
.Zarafonetis CJ, Dabich L, Skovronski JJ. Retrospective studies in scleroderma: skin response to potassium para-aminobenzoate therapy. Clin Exp Rheumatol 1988;6:261-268.
.Zarafonetis CJD, Grekin RH, Curtis AC, et al. Further studies on the treatment of lupus erythematosus with sodium para-aminobenzoate. J Invest Dermatol 1948;11:359.
.Zarafonetis CJD. Darkening of gray hair during para-amino-benzoic acid therapy. J Invest Dermatol 1950;15:399-401.
.Zarafonetis CJD. The treatment of scleroderma: results of potassium para-aminobenzoate therapy in 104 cases. In: Mills LC, Moyer JH, eds. Inflammation and diseases of connective tissue. Philadelphia: Saunders; 1961:688-696.
.Zarafonetis CJD. Treatment of Peyronie’s disease with potassium para-aminobenzoate. J Urol 1959;81:770-772.

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