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PubMed1993

Compartmentation of intestinal drug sulphoconjugation. Incorporation of luminal and contraluminal [35S]sulphate into 1-naphthol by the isolated mucosa of guinea pig jejunum and colon.

Compartmentation of 1-naphthol metabolism was inferred from the metabolite pattern and distribution in the isolated mucosa of guinea pig intestine mounted in a flux chamber (Sund and Lauterbach, Arch Pharmacol Toxicol 58: 74-83, 1986). To verify the existence of these compartments the dependence of [35S]sulphate incorporation into 1-naphthol sulphate on the side of administration of 1-naphthol and [35S]sulphate was determined. Isolated mucosae were pre-equilibrated with [35S]-sulphate (5 x 10(6) cpm/mumol, 1 mM) for 30 min and subsequently incubated for 15 min with 50 microM 1-naphthol. The three 1-naphthol sulphate fractions (luminal side, blood side and tissue) were assayed by HPLC and liquid scintillation counting; their specific activity was calculated as percentage of the specific activity of the inorganic sulphate administered. 1-Naphthol glucuronide was also measured. In jejunal experiments: after luminal administration of 1-naphthol, 1-naphthol sulphate appeared almost exclusively in the luminal solution; its specific activity approached 70% and 3%, when [35S]sulphate was added to the luminal and blood side, respectively. After introducing 1-naphthol and [35S]sulphate on the blood side, a high and similar specific activity of 50-60% was observed in all three 1-naphthol sulphate fractions (luminal and blood side, tissue) though adding [35S]sulphate to the lumen side decreased the specific activity to 10-20%. In experiments on colonic mucosa: a specific activity both of luminal and blood side 1-naphthol sulphate of more than 50% was observed with blood side [35S]sulphate irrespective of the side of 1-naphthol administration. When [35S]sulphate was placed on the luminal side the specific activity of blood side 1-naphthol sulphate dropped to only 3%, and that of luminal 1-naphthol sulphate ranged between 6% and 20%. Supplementary experiments in which mucosae were exposed to 1-naphthol and [35S]sulphate for 45 min without preincubation showed a tendency to decrease the lumen: blood distribution ratio of 1-naphthol sulphate. However, the general pattern of 1-naphthol sulphate specific activity remained unchanged. The experiments provide further evidence that the jejunal conjugation of phenolic drugs is being performed in two major compartments, which are accessible from the lumen ("luminal compartment") and blood ("systemic compartment") side. The luminal compartment seems practically inaccessible to blood side sulphate as is the systemic compartment for luminal 1-naphthol. In the colonic mucosa, a major "systemic compartment" receiving its sulphate from the blood side is the site for most of the events, but a minor "luminal compartment" seems to be involved as well.

Animals↗
PubMed1997

Urinary naphthols as an indicator of exposure to naphthalene.

OBJECTIVE: The relationship between exposure to naphthalene and urinary excretion of naphthols was examined. METHODS: Concentrations of naphthalene and naphthols in breathing-zone air during a workshift and 1-naphthol and 2-naphthol in urine collected after the workshift were determined for 102 male workers. Gas chromatography with a flame ionization detector (GC-FID) was used to determine the air concentration. Urine naphthols were extracted after acid hydrolysis by solid-phase extraction and separated by the GC-FID method. Naphthalene homologues in air and their metabolites in urine samples were identified by gas chromatography-mass spectrometry. RESULTS: 1-Naphthol, 2-naphthol and 1,4-naphthoquinone were identified in the urine samples. The time-weighted average concentrations of naphthalene and naphthols in the breathing-zone air showed that the exposure level of the workers was rather low. The geometric mean values were as follows: 0.77 and 0.87 mg/m3 for naphthalene, 0.016 and 0.034 mg/m3 for 1-naphthol, 0.012 and 0.067 mg/m3 for 2-naphthol during tar distillation and naphthalene oil distillation, respectively. The corresponding urinary concentrations of 1- and 2-naphthols were 693.1 and 264.4 micromol/mol and 264.4 and 297.7 micromol/mol creatinine, respectively. The correlation coefficients between the naphthol concentrations in urine and the breathing-zone air concentrations of naphthalene were statistically significant, varying in the range of 0.64--0.75 for 1-naphthol and 0.70--0.82 for 2-naphthol. There was linear dependence (r = 0.76) between the summary concentration of naphthols in urine and the naphthalene concentration in air. CONCLUSIONS: Workers in tar distillation and naphthalene distillation are exposed to rather low concentrations of naphthalene and methylated naphthalenes and naphthols. Naphthols and 1,4-naphthoquinone identified in the urine appear to be the products of the hydroxylation of naphthalene present in the breathing-zone air. These findings suggest that the summary concentration of naphthols in urine can be used as a biomarker for naphthalene exposure.

Adolescent↗
PubMed1999

A study for the proper application of urinary naphthols, new biomarkers for airborne polycyclic aromatic hydrocarbons.

Urinary naphthols, 1- and 2-naphthol, recently have been suggested as route-specific biomarkers for exposure to airborne polycyclic aromatic hydrocarbons. For the proper application of urinary naphthols as biomarkers, we studied effects of lifestyle on urinary naphthols levels in 119 Japanese male workers. After improving the detection limit of urinary naphthols up to 0.27 microg/L by high-resolution capillary gas chromatography/mass spectrometry/selected ion monitoring, urinary naphthols were detectable in approximately 90% of the subjects. Among detectable samples, the geometrical mean (GM) of urinary 1-naphthol concentration was 5.13 microg/L (geometrical standard deviation, GSD, 4.90), while the GM of urinary 2-naphthol concentration was 3.16 microg/L (GSD, 5.61). We observed that urinary 1- and 2-naphthol level were three- and sevenfold higher, respectively, among smokers than among nonsmokers (p < 0.01). The ratios of urinary 2-naphthol to 1-naphthol were significantly higher among smokers than nonsmokers (p < 0.05). The number of cigarettes smoked and urinary cotinine levels were also positively related to the concentration of urinary naphthols (p < 0.01), while other lifestyle factors, i.e., age and consumption of alcohol, greasy or salty food, sweets, fruits, vegetables, meat, or fish, were not. We also studied whether genetic polymorphisms of enzymes, which were involved in naphthalene metabolism, affected urinary naphthols levels. The cytochrome P450 (CYP) 1A1 exon 7 genetic polymorphism was not related to urinary naphthol levels. Among smokers, the subjects with c1/c2 or c2/c2 type of CYP2E1, which was determined by CYP2E1 RsaI polymorphism in 5'-flaking region, showed higher concentrations of urinary 2-naphthol than the subjects with c1/c1 type regardless of creatinine-correction (p < 0.05) and the subjects with glutathione S-transferase (GST) M1 deficient type showed higher concentrations of both urinary 1- and 2-naphthol than those with GSTM1 normal type but only without creatinine-correction (p < 0.05). Thus, when urinary naphthols are used as biomarkers, smoking and the genetic polymorphisms of CYP2E1 and GSTM1 should be considered.

Adult↗
PubMed2004

Simultaneous determination of 1- and 2-naphthol in human urine using on-line clean-up column-switching liquid chromatography-fluorescence detection.

We developed a new 3-D HPLC method for on-line clean-up and simultaneous quantification of two important naphthalene metabolites, 1-naphthol and 2-naphthol, in human urine. Except an enzymatic hydrolysis no further sample pre-treatment is necessary. The metabolites are stripped from urinary matrix by on-line extraction on a restricted access material pre-column (RAM RP-8), transferred in backflush mode onto a silica-based CN-(cyano)phase column for further purification from interfering substances. By another successive column switching step both analytes are transferred with a minimum of overlapping interferences onto a C12 bonded reversed phase column with trimethylsilyl endcapping where the final separation is carried out. The entire arrangement is software controlled. Eluting analytes are quantified by fluorescence detection (227/430 nm) after an external calibration. Within a total run time of 40 min we can selectively quantify both naphthols with detection limits in the lower ppb range (1.5 and 0.5 microg/l for 1- and 2-naphthol, respectively) with excellent reliability (ensured by precision, accuracy, matrix-independency and FIOH quality assurance program participation). First results on a collective of 53 occupationally non exposed subjects showed mean levels of 11.0 microg/l (1-naphthol) and 12.9 microg/l (2-naphthol). Among smokers (n=21) a significantly elevated mean level of urinary naphthols was determined (1-naphthol: 19.2 microg/l and 2-naphthol: 23.7 microg/l) in comparison to non smokers (n=32; 1-naphthol: 5.6 microg/l, 2-naphthol: 5.6 microg/l).

Chromatography, High Pressure Liquid↗
PubMed2001

Urinary 1-hydroxypyrene and 2-naphthol concentrations in male Koreans.

OBJECTIVE: Urinary 1-hydroxypyrene (1-OHP) has been used as a biological marker of exposure to polycyclic aromatic hydrocarbons (PAHs), and urinary 2-naphthol is suggested as a new marker for route-specific exposure to airborne PAHs. We analyzed urinary 1-OHP and 2-naphthol concentrations in 292 male Koreans (129 university students and 163 shipyard workers) to define the distribution pattern in Koreans with no or low occupational exposure to PAHs. METHOD: Histories of cigarette smoking and the eating of PAH-containing foods were obtained by a self-administered structured questionnaire. Urine samples were collected and urinary 1-OHP and 2-naphthol concentrations were measured using high-performance liquid chromatography (HPLC). RESULTS: The arithmetic (geometric) means of urinary 1-OHP and 2-naphthol concentrations for all students, expressed as micromoles per mole of creatinine, were 0.04 (0.04) and 3.12 (2.22), for non-smokers 0.03 (0.03) and 1.78 (1.30) and for smokers 0.05 (0.03) and 4.36 (3.62), respectively. Among shipyard workers, the arithmetic (geometric) means of urinary 1-OHP and 2-naphthol concentrations were 0.69 (0.31) and 4.37 (2.62) for all, 0.27 (0.18) and 2.46 (1.16) for nonsmokers, and 0.97 (0.44) and 5.60 (4.44) for smokers, respectively. Mean urinary 1-OHP and 2-naphthol concentrations differed significantly between nonsmokers and smokers both in students and in shipyard workers. In smokers, some variables related to smoking habit were positively correlated with urinary 1-OHP and with 2-naphthol concentrations. The latter showed better correlations with the variables related to smoking amount than the former. None of the food-related factors was significantly correlated with urinary 1-OHP or 2-naphthol concentration. CONCLUSION: These results suggest that urinary 2-naphthol concentration is more sensitively affected by smoking status than urinary 1-OHP concentration and that urinary 2-naphthol is a sensitive marker for low-level inhalation of PAHs.

Chromatography, High Pressure Liquid↗
PubMed1984

Mechanisms of toxic injury to isolated hepatocytes by 1-naphthol.

The mechanism(s) of toxicity of 1-naphthol and two of its possible metabolites, 1,2- and 1,4-naphthoquinone, to freshly isolated rat hepatocytes has been studied. 1-Naphthol and both naphthoquinones exhibited a dose-dependent toxicity to hepatocytes. [1-14C]-1-Naphthol was metabolised by hepatocytes predominantly to its glucuronic acid and sulphate ester conjugates, but small amounts of covalently bound products were also formed. Blebbing on the surface of the hepatocytes was observed following exposure to 1-naphthol and the naphthoquinones, together with a dose-dependent decrease in intracellular glutathione (GSH), which preceded the onset of cytotoxicity. The toxicity of 1-naphthol and the naphthoquinones was potentiated by dicoumarol, an inhibitor of DT-diaphorase (NAD(P)H:quinone oxidoreductase). This enhanced toxicity was accompanied by a greater amount of surface blebbing, an increased depletion of intracellular GSH, particularly in the case of 1-naphthol and 1,4-naphthoquinone, and a decreased metabolism of 1-naphthol to its conjugates with variable effects on the amount of covalently bound products formed. These results support the suggestion that the toxicity of 1-naphthol may be mediated by the formation of 1,2-naphthoquinone and/or 1,4-naphthoquinone, which may then be metabolised by one electron reduction to naphthosemiquinone radicals. These, in turn, may covalently bind to important cellular macromolecules or enter a redox cycle with molecular oxygen thereby generating active oxygen species. Both of these processes appear to play a role in producing the cytotoxic effects of 1-naphthol.

Animals↗
PubMed2000

Conjugation of 1-naphthol in primary cell cultures of rat ovarian cells.

The present study concerns conjugation of 1-naphthol in primary cultures of rat ovarian cells. Two phase II enzymes catalyzing conjugation, i.e. phenol sulfotransferase (P-SULT) and phenol UDP-glucuronosyltransferase (P-UGT), were measured using 1-naphthol as substrate. The rates of conjugation by the different cell types of the rat ovary were the same at low concentrations and short incubation times. However, after 20 h of incubation the rate of conjugation in cells isolated from ovaries enriched in corpora lutea (CL) exceeded the rate in cells isolated from ovaries enriched in preovulatory follicles. In addition, when the granulosa cells were removed from the preovulatory follicles, the rate of conjugation was 1.7-fold higher, i.e. in the theca/stroma cells. When the cells were incubated with 1-[14C]naphthol and conjugates were subsequently separated by thin-layer chromatography, naphthyl glucuronide was the only conjugate observed. Pentachlorophenol (PCP), a commonly used inhibitor of P-SULT, inhibited 1-naphthol conjugation 50% in cell cultures, as well as in microsomal preparations. alpha-Naphthoflavone (ANF) and ellipticine (ELP), both cytochrome P450 (CYP) inhibitors, affected the conjugation of 1-naphthol in different ways; ANF did not affect P-UGT activity in microsomal preparations, but inhibited 1-naphthol conjugation in cell cultures by as much as 90%. On the other hand, ELP inhibited the conjugation of 1-naphthol up to 99% in the cell cultures, but only 75% in microsomal fractions. Testosterone (TST) and estradiol inhibited this activity approximately equal 50% in both of these experimental systems. Clomiphene citrate (CLF), a drug used to induce ovulation and demonstrating both estrogenic and antiestrogenic effects, did not influence the conjugation of 1-naphthol significantly in the cell cultures. The present findings demonstrate that P-UGT is by far the major enzyme conjugating 1-naphthol in the rat ovary and that commonly used inhibitors of P-SULT and CYPs also inhibit P-UGT activity, either directly or via other mechanisms.

Animals↗
PubMed1985

Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats.

[14C]Naphthalene was given orally to rats with cannulated bile ducts and to germ-free rats. Bile and urine from the cannulated rats and urine from the germ-free rats contained no radioactive 1,2-dihydro-1-hydroxy-2-methylthionaphthalene and only trace amounts of radioactive naphthols or naphthol conjugates. Urine of control rats contained 4.6% of the 14C dose as naphthols and/or naphthol glucuronides. Appreciable quantities of 1- and 2-naphthol (7-20% of dose) and 1,2-dihydro-1-hydroxy-2-methylthionaphthalene (1-35% of dose) were in urine from rats dosed orally or intracecally with 1,2-dihydro-1-hydroxy-2-S-cysteinylnaphthalene and 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene. Apparently, in vivo, naphthols and methylthio-containing metabolites of naphthalene are formed during enterohepatic circulation of 1,2-dihydro-1-hydroxy-2-S-cysteinylnaphthalene and 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene in a process dependent upon intestinal microflora. A possible pathway for the formation of naphthols is aromatization of the precursor compounds by elimination of the appropriate substituent group from these metabolites. This discovery of the essential role of the intestinal microflora in the formation of naphthols from naphthalene indicates the existence of a novel pathway for hydroxylation of aromatic systems and challenges the current concept of the in vivo relevance of the in vitro production of naphthols from naphthalene 1,2-oxide.

Acetylcysteine↗
PubMedDate not supplied

Simultaneous determination of urinary 1- and 2-naphthols, 3- and 9-phenanthrols, and 1-pyrenol in coke oven workers.

A method was developed for simultaneous quantification of urinary 1- and 2-naphthols, 3- and 9-phenanthrols and 1-pyrenol using gas chromatography with mass spectrometry (GC-MS). This method was applied to urine samples from coke oven workers (n=28) and controls (n=22) from Northern China. Geometric mean levels of urinary 1-naphthol (58.8 microg l(-1)), 2-naphthol (34.1 microg l(-1)), 3-phenanthrol (7.35 microg l(-1)), 9-phenanthrol (1.28 microg l(-1)) and 1-pyrenol (25.4 microg l(-1)) were significantly higher among coke oven workers than controls. All the substances tested were highest among top-of-oven workers, who had 15-fold higher 1-naphthol, eight-fold higher 2-naphthol and 20-fold higher 1-pyrenol levels compared with controls. Using multiple linear regression models, 72.5% of the variation in 1- and 2-naphthol and 82.8% of the variation in 1-pyrenol were explained by the concentration of naphthalene or pyrene in the urine, the work category and the smoking intensity. Cigarette consumption significantly contributed to levels of urinary 1-pyrenol and naphthols, particularly 2-naphthol. A negative relationship between work category and the ratio of naphthols/1-pyrenol was observed among smokers. Our results suggest that urinary naphthols and phenanthrols reflect polycyclic aromatic hydrocarbon (PAH) exposure as well as the widely used 1-pyrenol, and that interactions between cigarette smoking and PAH exposure result in different patterns of metabolism for individual PAHs.

Adult↗
PubMed2001

Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations.

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.

Base Sequence↗
PubMed1997

Urinary 1-naphthol excretion in the assessment of exposure to creosote in an impregnation facility.

OBJECTIVES: This study explored the possibility of using urinary 1-naphthol excretion as a marker of complex exposure among workers handling creosote. METHODS: Urine specimens of 6 workers from a creosote impregnation plant, where railroad ties were impreganted with coal tar creosote, were collected during 1 workweek, and the concentration of 1-naphthol was determined. 1-Naphthol in spot urine samples of 5 occupationally nonexposed male smokers was used as the background reference. Concurrently, naphthalene and 10 different polycyclic aromatic hydrocarbons (PAH) were determined in personal air samples. RESULTS: The mean airborne exposure of the workers was 1.5 mg/m3 for vaporous naphthalene, 5.9 micrograms/m3 for particulate PAH and 1.4 micrograms/m3 for PAH with 4-6 aromatic rings. The mean urinary concentration of 1-naphthol at the end of the workshift was 20.5 (range 3.5-62.1) mumol/l, whereas the referents' urinary concentration was below the detection limit (0.07 mumol/l). Airborne naphthalene correlated fairly well with 1-naphthol when measured at the end of the shift (r = 0.745). CONCLUSIONS: This method of analysis for 1-naphthol is sufficiently sensitive for measuring low occupational exposures to naphthalene. Low background exposures are, however, unlikely to result in detectable urinary levels of 1-naphthol. Since naphthalene is the most abundant compound in creosote vapor, urinary 1-naphthol determination serves well as a biological marker of exposure to vaporous creosote. Urinary 1-naphthol alone is not, however, a suitable marker for inhalatory or cutaneous exposure to PAH originating from creosote.

Air Pollutants, Occupational↗
PubMed1985

Selective toxicity of 1-naphthol to human colorectal tumour tissue.

1-Naphthol was selectively toxic to human colorectal tumours compared to corresponding normal colonic tissue removed at surgery and maintained in short-term organ culture. Nineteen of 24 tumours studied have shown a significant differential response. Three human colonic adenocarcinoma xenografts, in the short-term organ culture system, displayed the same response to 1-naphthol as primary tumours removed at surgery. 1-Naphthol, 1,2- and 1,4-naphthoquinone were also toxic to two human colonic adenocarcinoma cell lines, LoVo and COLO 206. The selective toxicity of 1-naphthol is mediated in part through an accumulation of 1-naphthol in the tumour tissue due to impaired conjugation by the tumour. The higher concentrations of 1-naphthol may then exert their toxicity either directly or by formation of naphthoquinones. Some indirect evidence was obtained for the possible involvement of 1,2- or 1,4-naphthoquinone in the cytotoxicity of 1-naphthol. Our studies suggest that further studies are warranted of the possible use of 1-naphthol or related compounds as antitumour agents.

Cell Line↗