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PubMed2000

Phenolphthalein induces chromosome aberrations in human and Chinese hamster liver cells (CHEL) cultured in vitro.

Phenolphthalein is a nonprescription laxative agent that has been widely used during this century. Recent studies in animal models have shown that phenolphthalein has carcinogenic activity. In order to assess cytogenetic effects on human cells in vitro, we tested phenolphthalein in a chromosome aberration assay in human embryo cells derived from amniotic fluid. Our results show that phenolphthalein induces a significant increase in the frequency of chromosome aberrations in human cells. The lowest dose level at which the clastogenic effect is evident is 23.2 microg/ml. Similar positive results were obtained in a Chinese hamster liver cell line, which is metabolically competent to activate different classes of promutagens and procarcinogens into biologically active metabolites. Instead, parallel experiments in Chinese hamster ovary cells did not show any clastogenic effect due to phenolphthalein. These latter data suggested that phenolphthalein acts as a promutagen and must be metabolically activated to exert its clastogenic effect. Teratogenesis Carcinog. Mutagen. 20:209-217, 2000.

Amniotic Fluid↗

PubMedDate not supplied

Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (+/-) mice.

Epidemiology studies have indicated that many human cancers are influenced by environmental factors. Genetically altered mouse model systems offer us the opportunity to study the interaction of chemicals with genetic predisposition to cancer. Using the heterozygous p53-deficient (+/-) mouse, an animal model carrying one wild type p53 gene and one p53 null allele, we studied the effects of phenolphthalein on tumor induction and p53 gene alterations. Earlier studies showed that phenolphthalein caused carcinogenic effects in Fisher 344 rats and B6C3F1 mice after a 2-yr dosing period (Dunnick and Hailey, Cancer Res. 56: 4922-4926, 1996). The p53 (+/-) mice received phenolphthalein in the feed at concentrations of 200, 375, 750, 3,000, or 12,000 ppm (approximately 43, 84, 174, 689, or 2,375 mg/kg body weight/day or 129, 252, 522, 2,867, or 7,128 mg/m2 body surface area/day) for up to 6 mo. A target organ cancer site that accumulated p53 protein in the B6C3F1 mouse (i.e., thymic lymphoma) was also a target site for cancer in the p53 (+/-) mouse. In the p53 (+/-) mouse, treatment-related atypical hyperplasia and malignant lymphoma of thymic origin were seen in the control and dosed groups at a combined incidence of 0, 5, 5, 25, 100, and 95%, respectively. Twenty-one of the thymic lymphomas were examined for p53 gene changes, and all showed loss of the p53 wild type allele. Chemical-induced ovarian tumors in the B6C3F1 mouse showed no evidence for p53 protein accumulation and did not occur in the p53 (+/-) mouse. The p53-deficient (+/-) mouse model responded to phenolphthalein treatment with a carcinogenic response in the thymus after only 4 mo of dosing. This carcinogenic response took 2 yr to develop in the conventional B6C3F1 mouse bioassay. The p53-deficient (+/-) mouse is an important model for identifying a carcinogenic response after short-term (< 6 mo) exposures. Our studies show that exposure to phenolphthalein combined with a genetic predisposition to cancer can potentiate the carcinogenic process and cause p53 gene alterations, a gene alteration found in many human cancers.

Animals↗

PubMed1997

Phenolphthalein-induced toxic epidermal necrolysis.

OBJECTIVE: To report a case of phenolphthalein-induced toxic epidermal necrolysis (TEN) in a patient maintained on several other medications more commonly known to be associated with TEN. CASE SUMMARY: A 78-year-old white man presented with intractable lower back pain and constipation. On day 1 of admission, the patient exhibited a diffuse urticarial rash over his trunk and extremities. History revealed that the patient had taken a combination phenolphthalein/docusate sodium (Correctol) over-the-counter laxative 1 day prior to admission. He had a similar urticarial rash 1.5 years earlier with this product and was instructed not to use it. A biopsy was performed and evidence from light microscopic analysis of the tissue led to a diagnosis of TEN. Furosemide, spironolactone, allopurinol, and hydroxyurea were considered possible causes of the reaction and were discontinued. Despite this, the lesions worsened in severity. The patient subsequently responded well to intravenous antibiotics, intravenous corticosteroids, and local wound care. Furosemide, spironolactone, hydroxyurea, allopurinol, and docusate were all reintroduced without reactivation of the lesions. DISCUSSION: Phenolphthalein is the active ingredient in several over-the-counter laxative preparations and has only rarely been reported to cause TEN. (It is no longer contained in Correctol.) To our knowledge, this case report represents only the third description of laxative-induced TEN. Although this patient had been exposed to several other medications more commonly associated with TEN, his long-term tolerance of and uneventful rechallenge with these medications exclude them as potential catalysts to this drug reaction. The patient's previous rash and the temporal relation of this event and the ingestion of phenolphthalein, as well as the similarity of this case to other reports, point to phenolphthalein as the cause of TEN in this patient. CONCLUSIONS: TEN is a rare disorder that can be fatal in up to 30% of patients. Clinicians should include phenolphthalein in their list of possible causes of drug-induced TEN. A careful and complete medication history can help avoid unnecessary discontinuation of clinically important medications and inadvertent rechallenge with the causative agent.

Aged↗

PubMed2004

Ovarian cancer risk and use of phenolphthalein-containing laxatives.

PURPOSE: Experimental studies in rodents demonstrated the carcinogenic potential of phenolphthalein, the active ingredient in some laxatives, administered at doses similar to the dose that could be used by humans. Ovarian cancer was one of the cancers observed in these studies. We examined the association between epithelial ovarian cancer and use of phenolphthalein-containing laxatives in a population-based case-control study. METHODS: The study includes 356 epithelial ovarian cancer cases (256 invasive, 100 borderline) and 424 controls. Cases were identified through a population-based registry in Los Angeles County in 1992-1998, and controls were matched to cases by age, race/ethnicity and neighborhood. Data on laxative use (specific brands, frequency of use, usual dose) were obtained by structured in-person interview. RESULTS: Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of invasive ovarian cancer (odds ratio (OR) 1.1, 95% confidence interval (CI) 0.75, 1.5) or of borderline ovarian cancer (OR 0.75, 95%CI 0.37, 1.5). Total days used, mean number of pills per day and cumulative dose were also unrelated to risk. CONCLUSIONS: This study provides some assurance that phenolphthalein-containing laxatives do not increase the risk of ovarian cancer in humans. These findings are of particular importance to those countries in which phenolphthalein is still used in over-the-counter medications.

Adult↗

PubMed2001

Biliary excretion of phenolphthalein glucuronide in the rat.

To examine the substrate specificity of an ATP-dependent organic anion transporter, the multidrug resistance protein 2, we examined the effects of various bile acid conjugates and organic anions on the biliary excretion of phenolphthalein glucuronide, a hydrophilic glucuronide conjugate, in rats. Biliary phenolphthalein glucuronide excretion was markedly inhibited by taurolithocholate-3-sulfate and ursodeoxycholate-3-O-glucuronide. In contrast, ursodeoxycholate-3,7-disulfate and pravastatin only slightly inhibited and cefpiramide did not inhibit biliary phenolphthalein glucuronide excretion. Biliary excretion of sulfobromophthalein, leukotriene C(4) and pravastatin was inhibited by phenolphthalein glucuronide infusion to some extent. These findings suggest that phenolphthalein glucuronide is a relatively low affinity substrate for the multidrug resistance protein 2.

Journal Article↗

PubMed1997

Phenolphthalein-containing laxative use in relation to adenomatous colorectal polyps in three studies.

Phenolphthalein, the active ingredient in many laxatives, was recently found to be a carcinogen in animal models. Human data suggest a laxative-colon cancer association, but few data specifically address the effects of phenolthalein-containing laxatives. We examined use of phenolphtalein-containing laxatives in relation to occurrence of adenomatous colorectal polyps in data from three case-control studies. The study conducted in Los Angeles, California (1991-1993), and the two studies conducted in North Carolina (1988-1990 and 1992-1995) altogether included 866 cases and 1,066 controls. The prevalence of using phenolphthalein-containing laxatives at least once a week in the recent past, however, was less than 5% among these subjects. The multivariate-adjusted odds ratios associated with recent use of phenolphthalein-containing laxatives once a week or more were 1.8 -95% confidence interval (CI), 0.5-6.2] in Los Angeles, 1.0 (CI, 0.4-2.2) in North Carolina (1988-1990), and 1.1 (CI, 0.2-5.7) in North Carolina (1992-1995). For use of other types of laxatives, the corresponding odds ratios were 1.3 (CI, 0.9-1.9) in Los Angeles, 1.0 (CI, 0.5-1.7) in North Carolina (1988-1990), and 0.9 (CI, 0.4-1.8) in North Carolina (1992-1995). Although the low prevalence of frequent use made for relatively wide confidence intervals, overall these data suggest that use of phenolphthalein-containing laxatives does not increase risk of adenomatous colorectal polyps.

Adenomatous Polyps↗

PubMed2001

Simple quantification of ultrasonic intensity using aqueous solution of phenolphthalein.

Aqueous phenolphthalein solution under sonication was investigated for use as a chemical dosimeter. The fading time of aqueous phenolphthalein solution under sonication depended on the concentration of phenolphthalein and the pH values of solutions. The fading time was correlated to the ultrasonic intensity in a reaction vessel that is estimated on the basis of decomposition of porphyrin. The relation between the fading time and the ultrasonic intensity for different frequencies is expressed by a single curve. From these results, it is indicated that aqueous solutions of phenolphthalein is useful for simple quantification of ultrasonic intensity for practical use, and one can regard it as one of the ultrasonic intensity indicators.

Phenolphthalein↗

PubMed2000

Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives.

We examined ovarian cancer risk in relation to use of phenolphthalein-containing laxatives in 410 epithelial ovarian cancer cases and 713 controls. Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of ovarian cancer (odds ratio, OR, 1.1, 95% confidence interval, CI, 0.9-1.4). Risk was slightly, but not significantly, higher with more frequent use (OR 1.2 for 75 or more days of use). When women who used non-phenolphthalein containing laxatives was used as the reference group, the associations were slightly, but not significantly larger (OR 1.4 for any use of phenolphthalein-containing laxatives and OR 1.5 for 75 or more days of use)

Adult↗

PubMed2000

Toxicokinetics of phenolphthalein in male and female rats and mice.

Phenolphthalein (PTH), which has been used as the active ingredient in a number of prescription and over-the-counter laxative products, is a rodent chemical carcinogen in multiple organs in the NTP 2-year bioassay at doses of 291-2927 mg/kg. This paper describes the toxicokinetics and estimates the internal dose of PTH administered as a single iv or gavage dose, or ad libitum for 14 days in feed to F344 rats, B6C3F1 mice, p53 (+/-) mice, and C57BL mice at doses that bracketed those used in the bioassay. Plasma concentrations for free phenolphthalein (PTH-F) and phenolphthalein glucuronide (PTH-G) were obtained for each dose regimen. Total phenolphthalein (PTH-T) was calculated as the sum of the molar concentrations of PTH-F and PTH-G. Noncompartmental pharmacokinetic models were used to calculate the area under the curve (AUC) from 0 h to infinity (AUC(infinity)), clearance (Cl), and oral bioavailability (F) for PTH-F; and were used to calculate AUC(infinity), t((1/2)), and relative absorption (Q) for PTH-T. After iv administration, PTH-F rapidly declined in rats and mice; PTH-T rose rapidly to Cmax and slowly declined 6-8 h after dosing, with no sex-related differences for rats or mice. For feed studies, mean plasma concentration (f1.gif" BORDER="0">(infinity)) and 24-h area under the curve (AUC(24h)) values were calculated. Results from feed studies showed no dose response in rat plasma PTH-F above approximately 50 mg/kg. Rat PTH-T AUC(24h) and f1.gif" BORDER="0">(infinity) were linear with doses up to approximately 650 mg/kg. In B6C3F1 mice, PTH-F and PTH-T AUC(24h) increased nonlinearly with doses above approximately 165 mg/kg. PTH is well absorbed and readily converted to PTH-G when administered in feed to rats and mice, except at the highest bioassay doses, where PTH absorption may be saturated.

Animals↗

PubMed2003

Biliary excretion of phenolphthalein sulfate in rats.

Glucuronide and glutathione conjugates have been reported to be substrates of multidrug resistance protein 2 (Mrp2), whereas sulfates of nonbile acid organic anions have never been reported as substrates of Mrp2. To further examine the substrate specificity of Mrp2, we examined the effects of bile acid sulfates on the biliary excretion of phenolphthalein sulfate in rats. The biliary excretion of phenolphthalein sulfate was markedly delayed in Eisai hyperbilirubinemic rats, an Mrp2-deficient strain, and was markedly inhibited by taurolithocholate-3-sulfate. The biliary excretion of leukotriene C(4) metabolites and sulfobromophthalein was inhibited by phenolphthalein sulfate infusion to some extent. These findings suggest that phenolphthalein sulfate is a unique sulfated nonbile acid organic anion which is a substrate of Mrp2.

ATP-Binding Cassette Transporters↗

PubMed1977

[Critical observations on the use of phenolphthalein monophosphate as a substrate for the determination of prostatic acid phosphatase (author's transl)].

At pH 10, which is in the alkaline measurement range, phenolphthalein is bound by albumin. The resonance system of this acid-base indicator cannot therefore be completely formed, and the colour intensity is correspondingly lower. Albumin also binds phenolphthalein monophosphate at pH 4-8, in the pH range of the enzymic reaction. Depending on the relative concentrations, the substrate concentration is therefore either suboptimal (manifested as a lower catalytic concentration of phosphatase), or the substrate excess is bound by albumin, so that the substrate inhibition of the phosphatase is decreased or abolished. Binding of phenolphthalein and its monophosphate to albumin is partly prevented by the addition of alcohol. These results show that the determination of prostate phosphatase with the substrate phenolphthalein monophosphate is markedly influenced by various factors. The interpretation of the observed colour intensity is therefore difficult, and the calculation of the catalytic concentration is frequently subject to error.

Acid Phosphatase↗

PubMed1990

In vivo estrogenic and antiestrogenic activity of phenolphthalein and derivative compounds.

The estrogenic activity of phenolphthalein and other related triphenylmethane dyes was evaluated in vivo in the immature rat uterus. Phenolphthalein behaved as a partial agonist of estradiol in stimulating the growth of rat uterus. Other specific estrogenic effects of the dye included an increase of the uterine DNA content, histological changes and induction of estrogen-modulated secretory proteins. The progressive introduction of side chains in the triphenylmethane skeleton concomitantly decreased the estrogenic activity. Triphenylmethanes competed with [3H]estradiol for the binding to the estrogen receptor in vitro, the relative binding affinity being correlated with the estrogenic potency observed in vivo. Phenolphthalein also showed antiestrogenic activity that could be overcome by increasing the dose of estradiol.

Animals↗

PubMed1988

Potentiation by phenolphthalein of the responses of guinea-pig ileum and rat stomach strip to PGE2 and other agonists.

Phenolphthalein was examined for its effect on the activity of isolated muscle (guinea-pig ileum and colon, rat stomach), and on the tissue responses to PGE2, histamine and 5-HT. The ileal circular muscle and both muscle layers of the colon were unaffected by phenolphthalein. In contrast, the laxative potentiated the responses of the longitudinal muscle of guinea-pig isolated ileum and the rat stomach strip to the agonists, particularly PGE2. This potentiation was reduced by indomethacin in vivo, but mepyramine or methysergide had little or no effect. Augmentation of muscle activity by phenolphthalein, particularly in the response to PGE2, may contribute to the laxative effect.

Animals↗

PubMed2003

Lack of susceptibility of heterozygous p53-knockout CBA and CIEA mice to phenolphthalein in a 6-month carcinogenicity study.

Phenolphthalein has carcinogenic activity, causing malignant lymphomas in B6C3F1 mice at a dietary dose of 3000 ppm in a 2-year carcinogenicity study and in female heterozygous p53-knockout TSG mice (C57BL/6 background) at the same dose in a 6-month study. To examine whether carcinogenic potential of phenolphthalein can be detected in other p53-knockout mouse [p53 (+/-)] strains such as p53 (+/-) CBA mice or p53 (+/-) CIEA mice (C57BL/6 background) and their littermates, they were given a diet containing 0, 6000 or 12000 ppm for 6 months. Unequivocal induction of neoplastic lesions was not apparent, suggesting that p53 (+/-) CBA mice and p53 (+/-) CIEA mice are resistant to the induction of malignant lymphomas by the treatment of phenolphthalein.

Administration, Oral↗

PubMed2000

Lack of susceptibility of transgenic mice carrying the human c-Ha-ras proto-oncogene (rasH2 mice) to phenolphthalein in a 6-month carcinogenicity study.

Phenolphthalein has carcinogenic activity, causing malignant lymphomas in B6C3F1 mice at a dietary dose of 3000 ppm in a 2-year carcinogenicity study and in heterozygous p53-deficient female mice at the same dose in a 6-month study. To examine whether phenolphthalein carcinogenic potential can be detected in male and female transgenic (Tg) mice carrying the human c-Ha-ras gene (rasH2 mice) and their wild-type littermates (non-Tg mice), a diet containing 3000, 6000 or 12000 ppm was given for 6 months. Unequivocal induction of neoplastic lesions was not apparent, suggesting that rasH2 mice are resistant to the induction of malignant lymphomas by the treatment of phenolphthalein.

Adenoma, Liver Cell↗

PubMed1984

Phenolphthalein stimulates the formation of histamine, 5-hydroxytryptamine and prostaglandin-like material by rat jejunum, ileum and colon.

The effects of phenolphthalein on the formation of histamine, 5-hydroxytryptamine(5-HT) and prostaglandin-like material by rat intestine were examined in vivo. Phenolphthalein, in a dose that causes laxation increased the formation of histamine, 5-HT and prostaglandin-like material, and indomethacin reduced these increases. The data support the idea that the laxative effect of phenolphthalein is due to increased intestinal production of prostaglandin, histamine and 5-HT.

Animals↗

PubMed1984

Suppression of laxative action of phenolphthalein by orally-administered indomethacin or aspirin.

Oral administration of phenolphthalein produced a dose-dependent increase of wet faeces excreted by mice. The response to phenolphthalein was reduced by pretreatment with indomethacin, aspirin or polyphloretin phosphate (PPP), but not with benoxaprofen. These findings support the view that the effect of phenolphthalein may be suppressed by PG synthetase inhibitors (indomethacin, aspirin) and by PPP.

Administration, Oral↗

PubMed1980

Enterohepatic recycling of phenolphthalein, morphine, lysergic acid diethylamide (LSD) and diphenylacetic acid in the rat. Hydrolysis of glucuronic acid conjugates in the gut lumen.

1. Biliary elimination in female Wistar albino rats 3 h after i.p. injection of [3H]phenolphthalein, [3H]morphine, 14C-LSD and [14C]diphenylacetic acid was 90%, 45%, 75% and 57% respectively, predominantly as glucuronides. 2. Infusion of 3 h bile from the previous experiments into the duodena of bile-duct-cannulated animals demonstrated enterohepatic circulation, amounting in 24 h to 85%, 41%, 28% and 66% of the infused doses of the conjugates of phenolphthalein, morphine, LSD and diphenylacetic acid respectively. 3. Pretreatment with antibiotics to suppress intestinal microflora decreased this enterohepatic recirculation to 22%, 8.6% and 21% in 24 h for phenolphthalein, morphine and diphenylacetic acid glucuronides respectively. Antibiotic pretreatment did not influence the absorption and re-excretion of infused doses of the free aglycones, thus demonstrating the importance of bacterial beta-glucuronidase hydrolysis of the biliary conjugates. 4. The extent of intestinal absorption of the aglycones after bacterial beta-glucuronidase hydrolysis of the conjugates is related to their lipid-solubility as estimated by octan-1-ol:0.1 M phosphate buffer partition ratios (P-values). 5. The persistence of compounds in the enterohepatic circulation is determined by the faecal and urinary elimination of the circulating compounds. Faecal elimination is governed by the extent of intestinal absorption of the circulating compounds, which is influenced by the efficacy of intestinal hydrolysis of the conjugates and the relative lipophilicity of the aglycones released.

Animals↗