Disposition and Metabolism of 14C-Solvent Yellow and Solvent Green Aerosols after Inhalation

Disposition and Metabolism of l4C-Solvent Yellow and SolventGreen Aerosols after Inhalation. MEDINSKY, M. A., CHENG, Y.S., KAMPCIK, S. J., HENDERSON, R. F., AND DUTCHER, J. S. (1986).Fundam. Appl. Toxicol. 7, 170-178. Solvent yellow (2-(2'-quinolinyl)-l,3-indandione)and solvent green (1,4-di-p-toluidinoanthraquinone) are componentsof colored smoke munitions and may become airborne and be inhaledby workers during the manufacture of the munitions. Little isknown about the disposition of either dye after inhalation.To obtain this information, we exposed male F344/N rats to ¹⁴C-solventyellow aerosols (160 nmol solvent yellow/liter air) or a mixtureof ¹⁴C-solvent yellow and unlabeled solvent green (340 nmolsolvent yellow and 370 nmol solvent green/liter air) for 60min. After either exposure, solvent yellow was rapidly clearedfrom the respiratory tract, with a t of 2–3 hr. Solventgreen was retained in the lungs with a minimum estimated 11/2for clearance of 22 days. Solvent green was not detected inother tissues during the 70-hr postexposure period. After eitherexposure, high-pressure liquid chromatography analysis of tissuesextracts indicated that 40 to 75% of the ¹⁴C in liver and kidneyconsisted of solvent yellow metabolites. Greater than 90% ofthe ¹⁴4C in the lungs was unmetabolized solvent yellow. Themajor pathway for excretion of solvent yellow and solvent yellowmetabolites was the feces (74% of the initial body burden);the 11/2 for excretion was 14 hr. Urinary ¹⁴C accounted for14% of the initial body burden and the 11/2 for excretion was10 hr. Over 90% of the ¹⁴C excreted in the urine was solventyellow metabolites. Very little solvent yellow (2%) was metabolizedto ¹⁴CO2. By 72 hr after exposure, only 10% of the initial ¹⁴Cdeposited remained in the body.     

Comparative Carcinogenicity,Metabolism, Mutagenicity,and DNA Binding of 7H-Dibenzo[c,g]carbazole and Dibenz[a,j]acridine

Abstract

Complex mixtures that are produced from the combustion of organic materials have been associated with increased cancer mortality. These mixtures contain homocyclic and heterocyclic polycyclic aromatic hydrocarbons (PAHs), many of which are known carcinogens. In particular,N-heterocyclic aromatic compounds (NHA) are present in these mixtures. Studies to determine the metabolic activation of these compounds have been undertaken. The purpose of this review is to compare and contrast the metabolic activation and biological effects of two NHA, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA), in order to better assess the contribution of NHA to the carcinogenic potency of complex mixtures and to develop biomarkers of the carcinogenic process. DBC has both local and systemic effects in the mouse; it is a potent skin and liver carcinogen following topical application and a lung carcinogen following i.p. application. On the other hand, DBA is a moderate mouse skin carcinogen following topical application and a lung carcinogen following subcutaneous injection. The biological differences for DBC and DBA are reflected in target organ-specific proximate and mutagenic metabolites and DNA adduct patterns.     

Disposition of [14C]methyl bromide in rats after inhalation

Methyl bromide is used as a disinfectant to fumigate soil and a wide range of stored food commodities in warehouses and mills. Human exposure occurs during the manufacture and use of the chemical. The purpose of this investigation was to determine the disposition and metabolism of [14C]methyl bromide in rats after inhalation. Male Fischer-344 rats were exposed nose only to a vapor concentration of 337 nmol [14C]methyl bromide/liter air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Elimination of 14C as 14CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total [14C]methyl bromide absorbed excreted by this route. CO2 excretion exhibited a biphasic elimination pattern with 85% of the 14CO2 being excreted with a half-time of 3.9 +/- 0.1 hr (means +/- SE) and 15% excreted with a half-time of 11.4 +/- 0.2 hr. Half-times for elimination of 14C in urine and feces were 9.6 +/- 0.1 and 16.1 +/- 0.1 hr, respectively. By 65 hr after exposure, about 75% of the initial radioactivity had been excreted with 25% remaining in the body. Radioactivity was widely distributed in tissues immediately following exposure with lung (250 nmol equivalents/g), adrenal (240 nmol equivalents/g), kidney (180 nmol equivalents/g), liver (130 nmol equivalents/g), and nasal turbinates (110 nmol equivalents/g) containing the highest concentrations of 14C. Radioactivity in livers immediately after exposure accounted for about 17% of the absorbed methyl bromide. Radioactivity in all other tissues examined accounted for about 10% of the absorbed methyl bromide. Elimination half-times of 14C from tissues were on the order of 1.5 to 8 hr. In all tissues examined, over 90% of the 14C in the tissues was methyl bromide metabolites. The data from this study indicate that after inhalation methyl bromide is rapidly metabolized in tissues and readily excreted.     

Disposition of [14C]pinacidil in humans

Pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate] is a novel, direct-acting vasodilator antihypertensive agent. The cyano 14C-labeled drug is rapidly and completely absorbed after an oral 12.5-mg dose in solution. The blood:plasma concentration ratios (0.8-0.9) indicate transient penetration of radioactivity into blood cells. Blood and plasma tmax (0.5 h) and t 1/2 (4 h) of [14C]pinacidil equivalents are similar. Pinacidil (51%), pinacidil N-oxide (28%), and unidentified polar metabolites (21%) comprise the plasma radioactivity. The plasma t 1/2 of pinacidil is 2-3 h, and that of pinacidil N-oxide is 4-5 h. Renal excretion of radioactivity is the major route (80-90% dose) of drug elimination; fecal elimination accounted for 4% of the dose. Renal clearance of the N-oxide is 10 times the renal clearance of the parent drug and exceeds the creatinine clearance. Biotransformation products in 0-24-h urine samples include pinacidil (10%), pinacidil N-oxide (60%), and free and conjugated analogues of pinacidil and metabolites (30%). Stereoselective metabolism is not a major biotransformation pathway of pinacidil or the N-oxide metabolite.     

Synthesis and characterization of monohydroxylated derivatives of 7H-dibenzo[c,g]carbazole.

The synthesis of several monohydroxylated derivatives of the potent carcinogen 7H-dibenzo[c,g]carbazole (DBC), including 1-hydroxy-7H-dibenzo[c,g]carbazole (1-OH-DBC), 13-c-hydroxydibenzo[c,g]carbazole (13-c-OH-DBC), and 5-hydroxy-7H-dibenzo[c,g]carbazole (5-OH-DBC), is described. 1-OH-DBC was prepared from 8-methoxy-2-tetralone and 2-naphthyl-hydrazine via Fischer indole synthesis followed by boron tribromide demethylation. The rearrangement and hydrolysis reactions to give 13-c-OH-DBC from DBC and benzoyl peroxide are discussed. The preparation and isolation of 5-OH-DBC, by hydrolysis of 5-acetoxy-N-acetyl-DBC, and the formation of its intermediate 5-acetoxy-DBC and its byproduct 6,6'-bis-(5-OH-DBC) are described in detail.     

Disposition of [14C]ruboxistaurin in humans.

Ruboxistaurin is a potent and specific inhibitor of the beta isoforms of protein kinase C (PKC) that is being developed for the treatment of diabetic microvascular complications. The disposition of [(14)C]ruboxistaurin was determined in six healthy male subjects who received a single oral dose of 64 mg of [(14)C]ruboxistaurin in solution. There were no clinically significant adverse events during the study. Whole blood, urine, and feces were collected at frequent intervals after dosing. Metabolites were profiled by high performance liquid chromatography with radiometric detection. The total mean recovery of the radioactive dose was approximately 87%, with the majority of the radioactivity (82.6 +/- 1.1%) recovered in the feces. Urine was a minor pathway of elimination (4.1 +/- 0.3%). The major route of ruboxistaurin metabolism was to the N-desmethyl ruboxistaurin metabolite (LY338522), which has been shown to be active and equipotent to ruboxistaurin in the inhibition of PKC(beta). In addition, multiple hydroxylated metabolites were identified by liquid chromatography-mass spectrometry in all matrices. Pharmacokinetics were conducted for both ruboxistaurin and LY338522 (N-desmethyl ruboxistaurin, 1). These moieties together accounted for approximately 52% of the radiocarbon measured in the plasma. The excreted radioactivity was profiled using radiochromatography, and approximately 31% was structurally characterized as ruboxistaurin or N-desmethyl ruboxistaurin. These data demonstrate that ruboxistaurin is metabolized primarily to N-desmethyl ruboxistaurin (1) and multiple other oxidation products, and is excreted primarily in the feces.     

Disposition of [14C]Dimercaptosuccinic Acid in Mice

Disposition of [¹⁴C]Dimercaptosuccinic Acid in Mice. LIANG,Y.-Y., MARLOWE, C., AND WADDELL, W. J. (1986). Fundam. Appl.Toxicol. 6, 532–540. Dimercaptosuccinic acid labeled with¹⁴C ([¹⁴C]DMSA) was administered to mice iv; the mice were frozenby immersion in dry ice/hexane at 6 and 20 min and 1, 3, 9,and 24 hr after injection. The frozen mice were sectioned andprocessed for whole-body autoradiography for soluble substances.The radioactivity was highly localized in extracellular fluidssuch as the subcutaneous, intrapleural, intraperitoneal, andperiosteal spaces. There was a pronounced accumulation in theperiosteal fluid above that in other fluids during the firsthour after injection. Most of the radioactivity was eliminatedby the kidney and liver. Pretreatment of a mouse with HgCl₂subcutaneously 1 hr before [¹⁴C [¹⁴C]DMSA produced an increasein radioactivity in the liver and decrease in lung. A high concentrationof radioactivity was seen at the subcutaneous site of injectionof the HgCl₂. The results are interpreted to indicate that mostof the DMSA is in the extracellular space but that it can crosscellular membranes to some extent. The pronounced accumulationin periosteal fluid may be an interaction of DMSA with Ca²⁺in this space. No tissue had a pronounced retention of the compound,but lung retained more than most other tissues.     

Disposition and metabolism of [14C]loperamide in rats

Following oral administration of [14C]loperamide hydrochloride in 1 mg/kg to rats, plasma levels of radioactivity reached maximum at 4 hrs and decreased with a half-life of 4.1 hrs. Radioactivity in 96-hr feces accounted for 95% of the dose, with 30% associated with unchanged drug, while that in urine only 3.5%. Radioactivity in 48-hr bile accounted for 42% of the dose associated entirely with metabolites. 3% of the dose was found at the level of the enterohepatic cycles. These findings show that about 70% of the dose with absorbed by intestine, the target tissue of the drug, a portion (30%) of which was excreted back into intestinal cavity after demethylation, while the remaining 40% transferred to liver by which it was extracted mostly, metabolized extensively and excreted largely into bile, as supported by in vitro demethylating activity in gut segments but none in gut contents, and by in situ marked hepatic extraction of the drug. Main metabolic pathways involved are described.     

Disposition of [14C]povidone after oral administration to the rat

The tissue distribution and excretion of 14C-labelled povidone (polyvinylpyrrolidone; K-30; average mol wt 40,000) was studied in male Sprague-Dawley rats given a single oral dose. The major pathway of elimination of radioactivity was in the faeces, in which 90.8% of the administered dose was recovered after 12 hr and 98.4% after 48 hr. Amounts of radioactivity in major tissues and in the blood were not significantly different from those in untreated controls. A minor amount of radioactivity, representing 0.04% of the administered dose, was detected in the urine after 6 hr. Dialysis studies of [14C]povidone suggested that the absorbed species was a low-molecular-weight (less than 3500) oligomer. It was concluded that an oral dose of [14C]povidone is not significantly absorbed in the rat.     

Disposition and metabolism of 2,3-[14C]dichloropropene in rats after inhalation

2,3-Dichloropropene (2,3-DCP) is a constituent of some commercially available preplant soil fumigants for the control of plant parasitic nematodes. Human exposure potential exists during manufacture of the chemicals or during bulk handling activities. The purpose of this investigation was to determine the disposition and metabolism of 2,3-[14C]DCP in rats after inhalation. Male Fischer-344 rats were exposed nose-only to a vapor concentration of 250 nmol 2,3-[14C]DCP/liter air (7.5 ppm; 25 degrees C, 620 Torr) for 6 hr. Blood samples were taken during exposure, and urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Urinary excretion was the major route of elimination of 14C (55% of estimated absorbed 2,3-DCP). Half-time for elimination of 14C in urine was 9.8 +/- 0.05 hr (means +/- SE). Half-time for elimination of 14C feces (17% of absorbed 2,3-DCP) was 12.9 +/- 0.14 hr (means +/- SE). Approximately 1 and 3% of the estimated absorbed 2,3-[14C]DCP were exhaled as either 2,3-[14C]DCP or 14CO2, respectively. Concentrations of 14C in blood increased during 240 min of exposure, after which no further increases in blood concentration of 14C were seen. 14C was widely distributed in tissues analyzed after a 6-hr exposure of rats to 2,3-[14C]DCP. Urinary bladder (150 nmol/g), nasal turbinates (125 nmol/g), kidneys (84 nmol/g), small intestine (61 nmol/g), and liver (35 nmol/g) were tissues with the highest concentrations of 14C immediately after exposure. Over 90% of the 14C in tissues analyzed was 2,3-DCP metabolites. Half-times for elimination of 14C from tissues examined ranged from 3 to 11 hr. The data from this study indicate that after inhalation 2,3-DCP is metabolized in tissues and readily excreted.     

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhalation studies on the biotransformation and elimination of [14C] trichlorofluoromethane and [14C] dichlorodifluoromethane in beagles

The possible biotransformation of trichlorofluoromethane (FC-11) and dichlorodifluoromethane (FC-12) was investigated in 4 male and 2 female adult Beagles after a short (6- to 20-min) inhalation. Dogs were anesthetized with ketamine and succinylcholine, intubated, and ventilated artificially. Trichlorofluoromethane (1000–5000 ppm, $\text{v}\text{v}$) or dichlorodifluoromethane 38000–12,000 ppm, $\text{v}\text{v}$) containing up to 180μ Ci of $\text{[}{}^{14}\text{C}\text{]}\text{fluorocarbon}$ was delivered from 110-liter Teflon bags, and all exhalations were collected via a nonrebreathing valve in similar bags for 1 hr. Venous blood samples were withdrawn at appropriate times and assayed for fluorocarbon-associated radioactivity. Exhalation bags were assayed for $\text{[}{}^{14}\text{C}\text{]}\text{fluorocarbon}$ and ¹⁴CO₂. Urine was collected for up to 3 days and assayed for ${}^{14}\text{C}$ metabolites as nonvolatile radioactivity. In some experiments animals were sacrificed 24 hr after exposure and tissues were removed for determination of nonvolatile radioactivity. Essentially all of the administered (inhaled) fluorocarbon was recovered in the exhaled air within 1 hr. Only traces of radioactivity were found in urine or exhaled carbon dioxide. All tissues contained measurable concentrations of nonvolatile radioactivity 24 hr after exposure but together represented less than 1% of the administered dose. It is not possible to determine if these trace levels are associated with metabolites of the fluorocarbons or with the unavoidable radiolabeled impurities present in the administered gas mixture. Neither phenobarbital pretreatment (60 mg/day for 3 days) nor prolonged exposure (50–90 min) produced any alteration of these results. Thus, it can be concluded that FC-11 and FC-12 are relatively refractory to biotransformation after a short inhalation exposure and that they are rapidly exhaled in their unaltered chemical form.     

Metabolism of [14C]Acetylisoniazid and [14C]Acetylhydrazine by the Rat and Rabbit

Metabolism of [¹⁴C]Acetylisoniazid and [¹⁴C]Acctylhydrazineby the Rat and Rabbit Thomas, B. H., WHITEHOUSE, L. W., andZEITZ, W. (1984). Fundam. Appl. Toxicol. 4, 646–653. Malerats and rabbits were singly dosed with either l-[¹⁴C]acetylisoniazid (acetylisonicotinoylhydrazine, acctyl-INH, 200 mg/kgpo) or 1-[^l4C]acetylhydrazine (50 or 100 mg/kg ip). Urine andexpired ¹⁴CO₂ were collected, and after 6 hr the animals werekilled for the analysis of tissue ¹⁴C concentrations and covalentbinding of ¹⁴C to hepatic protein. Rats excreted proportionatelymore ¹⁴C in urine and had lower ¹⁴C levels in their tissuescompared to rabbits. When acetyl-INH was administered, covalenthepatic protein binding of the acetyl moiety was greater inthe rabbit than the rat, but the opposite was observed whenacetylhydrazine was administered. Analysis of blood and urineby TLC revealed that the rabbit more rapidly metabolized bothacetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazinethan did the rat. These observations suggest that higher amidaseactivity in the rabbit compared to the rat leads to faster conversionof acetyl-INH to acetylhydrazine which in turn leads to greatercovalent binding and hepatotoxicity.     

Cholestyramine-Enhanced Fecal Elimination of Carbon-14 in Rats after Administration of Ammonium [14C]Perfluorooctanoate or Potassium [14C]Perfluorooctanesulfonate

Cholestyramine-Enhanced Fecal Elimination of Carbon-14 in Ratsafter Administration of Ammonium [¹⁴C]Perfluorooctanoate orPotassium [^l4C]Perfluorooctanesulfonate. JOHNSON, J. D., GIBSON,S. J., AND OBER, R. E. (1984). Fundam. Appl. Toxicol. 4, 972–976.After a single intravenous dose of ammonium [^l4C]perfluorooctanoate([¹⁴C]PFO, 13.3 mg/kg) or of potassium [¹⁴C]perfluorocctanesulfonate([¹⁴C]PFOS, 3.4 mg/kg) to rats, cholestyramine fed daily asa 4% mixture in feed was shown to increase the total carbon-14eliminated via feces and to decrease liver concentration ofcarbon-14. Rats were fed cholestyramine in feed for 14 daysafter administration of [¹⁴C]PFO and for 21 days after administrationof [¹⁴C]PFOS. Control rats were administered radiolabeled fluorochemicalbut were not treated with cholestyramine. Cholestyramine treatmentincreased mean cumulative carbon-14 elimination in feces by9.8-fold for rats administered [¹⁴C]PFO and by 9.5-fold forrats administered [¹⁴C]PFOS. After [¹⁴C]PFO, a mean of 4% ofthe dose of carbon-14 was in liver of cholcstyramine-trcatedrats at 14 days versus 7.6% in control rats; after [¹⁴C]PFOS,11.3% of the dose was in liver at 21 days versus 40.3% in controlrats. After administration of either radiolabeled compound,plasma and red blood cell carbon-14 concentrations, which wererelatively lower than liver concentrations, were also significantlyreduced by cholestyramine treatment.     

Disposition and metabolism of [14C]sparfloxacin after repeated administration in the rat.

Disposition and metabolism of [carbonyl-14C]sparfloxacin (SPFX, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, AT-4140; CAS 110871-86-8), a novel antimicrobial quinolone, were studied in rats during and after 14 consecutive daily oral administrations at 10 mg/kg. Plasma levels after the 1st and 14th administration were similar in terms of tmax (1 h), Cmax (around 1.35 micrograms eq/ml), T1/2 (3-4 h) and AUC (about 7.3 micrograms eq h/ml). Plasma levels at 0.5 h after each administration were virtually constant in the range of 1.25-2.66 micrograms eq/ml for 14 days, but those at 24 h tended to elevate to about 0.06 micrograms eq/ml, which was an apparent steady state level after the 6th administration. Tissue distribution after the repeated administration was also similar to that after single administration: levels in the kidney, liver, pancreas, submaxillary gland, lung and many others were higher than, or similar to those in plasma, and in brain and some others, lower. Composition of radioactive metabolites in urine was not statistically different from that after single administration. About 20 and 73% of dose were excreted in daily urine and feces, respectively, for 14 days and radioactivity was almost completely excreted within 96 h after the last administration.     

Disposition and metabolism of [14C]-amezinium metilsulfate in rats

Disposition and metabolism of [14C]-amezinium metilsulfate (4-amino-6-methoxy-1-phenylpyridazinium methylsulfate, Risumic) were systematically studied in rats after intravenous (5 mg/kg) or oral (20, 100 mg/kg) administration. After oral administration at 20 mg/kg, blood level reached the maximum (Cmax) of 0.65 microgram eq/ml at 3 h (tmax) and decreased with t1/2 of 8.1 h. Levels in plasma and most tissues elevated to the Cmax at 3 h. The liver level was the highest (61 times as high as plasma level) of all examined tissues. Most tissue levels decreased thereafter essentially in parallel with plasma levels. The findings by whole-body autoradiography essentially agreed with those by radiometry. In lactating rats, milk levels were virtually similar to plasma levels. [14C]-Amezinium metilsulfate radioactivity in fetus and fetal blood was around 0.3 microgram eq/g, being about 1/10 level of maternal plasma level. About 24, 72 and 42% were excreted in urine, feces and bile, respectively. Re-absorption of biliary metabolites accounted for about 31%, being about 13% of orally given [14C]-amezinium metilsulfate. Plasma and aorta contained unchanged amezinium and glucuronide of hydroxyl amezinium MIII. In the brain, the major metabolite was O-demethyl amezinium MV and unchanged drug was not detected. Urinary metabolites were largely MIII glucuronide and the unchanged drug. Biliary metabolite was found composed mostly from MIII glucuronide. In feces, MIII and the unchanged amezinium were found. MIII and its glucuronide were novel metabolites which were identified by thin-layer chromatography and mass spectrometry.     

In vitro toxicity of 7H-dibenzo[c,g]carbazole in human liver cell lines.

7H-Dibenzo[c,g]carbazole (DBC) is a model N-heterocyclic aromatic compound (NHA) which is both a hepatotoxin and hepatocarcinogen in rodents. The focus of this investigation was to determine whether human liver cell lines display differential sensitivities to DBC-induced toxicity. Treatment of cell lines with increasing DBC concentrations produced apoptosis only in HepG2 cells. Although DBC inhibited the clonogenic growth of all cell lines at high concentrations, only the survival of HepG2 cells was reduced at lower concentrations. DBC inhibited DNA synthesis in two (HepG2, HLF) of the three cell lines at lower concentrations and was effective only at a high concentration in Mahlavu cells. Differences in DBC uptake were not observed in any of the cell lines, suggesting that bioavailability was not a limiting factor. DBC-DNA adducts were not detected in HLF or Mahlavu cells at either low or high concentrations of DBC. Consistent with the DNA adduct data, RP-HPLC analysis indicated that DBC was metabolized to a lesser degree in the HLF and Mahlavu cells. These results suggest that human liver cell lines differ markedly in the ability to metabolize DBC to toxic species and that DBC-induced apoptosis is only observed in cells that produce detectable metabolites and DBC-DNA adducts.