3-Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum.

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains ofPlasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.

Comparison of in vivo derived and scaled in vitro metabolic rate constants for several volatile organic compounds (VOCs).

Metabolic rate parameters estimation using in vitro data is necessary due to numbers of chemicals for which data are needed, trend towards minimizing laboratory animal use, and limited opportunity to collect data in human subjects. We evaluated how well metabolic rate parameters derived from in vitro data predict overall in vivo metabolism for a set of environmental chemicals for which well validated and established methods exist. We compared values of VmaxC derived from in vivo vapor uptake studies with estimates of VmaxC scaled up from in vitro hepatic microsomal metabolism studies for VOCs for which data were available in male F344 rats. For 6 of 7 VOCs, differences between the in vivo and scaled up in vitro VmaxC estimates were less than 2.6-fold. For bromodichloromethane (BDCM), the in vivo derived VmaxC was approximately 4.4-fold higher than the in vitro derived and scaled up VmaxC. The more rapid rate of BDCM metabolism estimated based in vivo studies suggests other factors such as extrahepatic metabolism, binding or other non-specific losses making a significant contribution to overall clearance. Systematic and reliable utilization of scaled up in vitro biotransformation rate parameters in PBPK models will require development of methods to predict cases in which extrahepatic metabolism and binding as well as other factors are likely to be significant contributors.

The Human Fecal Microbiota Metabolizes Foodborne Heterocyclic Aromatic Amines by Reuterin Conjugation and Further Transformations.

SCOPE: Heterocyclic aromatic amines (HAAs) are process-induced food contaminants with high mutagenic and/or carcinogenic potential. Although the human gut microbiota is known to affect the metabolism of dietary constituents, its impact on HAA metabolism and toxicity has been little studied. Here, the glycerol-dependent metabolism of seven foodborne HAAs (AαC, Trp-P-1, harman, norharman, PhIP, MeIQx, and MeIQ) by the human fecal microbiota is investigated. METHODS AND RESULTS: As analyzed by HPLC-DAD/FLD, the extent of conversion is strongly dependent on glycerol supplementation and HAA structure. AαC (60-100%) and the 2-aminoimidazoazarenes (up to 58%) are especially prone to microbial conversion. Based on high-resolution MS and/or NMR spectroscopy data, 70 fecal metabolites are identified in total, mainly formed by chemical reactions with one or two molecules of microbially derived reuterin. Moreover, it has been demonstrated that the human fecal microbiota can further transform reuterin adducts by reduction and/or hydroxylation reactions. Upon isolation, some reuterin-induced HAA metabolites appear to be partially unstable, complicating structural identification. CONCLUSION: The formation of microbial metabolites needs to be incorporated into risk assessment considerations for HAAs in human health. In this study, several HAA metabolites, mainly reuterin-dependent, are identified in vitro, providing the basis for future human studies investigating microbial HAA metabolism.

Distribution of 1,2-dichloropropane in blood and other tissues of rats after oral administration.

The present investigation was undertaken to determine the distribution of 1,2-dichloropropane (DCP) in the blood, liver, kidney, lung, and abdominal fat of rats after oral administration. Male rats were orally administered 62 or 125 mg/kg body weight doses of DCP dissolved in corn oil by gavage, and the concentrations in the blood and tissues were measured. The DCP concentration in the abdominal fat was much greater than in the blood and other tissues. Twenty-four-hr after oral administration, DCP could still be detected in the blood and abdominal fat in the 62-mg/kg group, and in the blood, liver, kidney, lung, and abdominal fat in the 125-mg/kg group. Our results are valuable data pertaining to the pharmacokinetics of DCP and to human health risk assessment of oral exposure to DCP.

Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis.

Recently, the International Agency for Research on Cancer issued a warning about the carcinogenicity of 1,2-dichloropropane (1,2-DCP) to humans based on an epidemiological study suggesting a relationship between the incidence of cholangiocarcinoma and occupational exposure to halogenated hydrocarbon solvent comprised mostly of 1,2-DCP. Although this dihaloalkane has been used in various industrial fields, there has been no biological evidence explaining the cholangiocarcinoma latency, as well as little understanding of general cholangiocarcinoma risk. In the present study, we explored the biliary excretion of 1,2-DCP metabolites by an untargeted metabolomics approach and the related molecular mechanism with in vitro and in vivo experiments. We hypothesized that the biliary excretion of carcinogens derived from 1,2-DCP contribute to the increased cholangiocarcinoma risk. We found that 1,2-DCP was conjugated with glutathione in the liver, and that the glutathione-conjugated forms of 1,2-DCP, including a potential carcinogen that contains a chloride atom, were excreted into bile by the bile canalicular membrane transporter, ABCC2. These results may reflect a risk in the backfiring of biliary excretion as a connatural detoxification systems for xenobiotics. Our findings would contribute to uncover the latent mechanism by which the chronic exposure to 1,2-DCP increases cholangiocarcinoma risk and future understanding of cholangiocarcinoma biology.

Quantitative determination of 2-amino-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)propane-1,3-diol and its active phosphorylated metabolite in rat blood by LC-MS/MS and application to PK/PD analysis.

A sensitive and specific LC-MS/MS method was developed and validated for simultaneous determination of 2-amino-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)propane-1,3-diol (SYL930) and its active phosphate metabolite (SYL930-P) in rat blood using SYL927, an analogue of SYL930 as the internal standard. Blood samples were prepared by a simple protein precipitation with acetonitrile. The chromatographic separation was performed on a ZorbaxSB-C18 column (3.5 µm, 2.1 × 100 mm) with a gradient mobile phase of methanol/water containing 0.1 % formic acid (v/v) at a flow rate of 0.2 mL/min. The detection was carried out on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) in multiple reactions monitoring mode (MRM). The monitored transitions were 381.2 → 364.2 for SYL930, 461.2 → 334.2 for SYL930-P, and 367.1 → 350.4 for the internal standard, respectively. Good linearity was obtained for the analytes over the range of 0.2-100 ng/mL for SYL930 and 0.5-100 ng/mL for SYL930-P. The lower limits of quantitation (LLOQs) for SYL930 and SYL930-P were 0.2 and 0.5 ng/mL, respectively. The intra-day and inter-day precisions (RSD, %) of analytes were within 9.87 %, and the accuracy (RE, %) ranged from -7.04 to 13.15 %. The mean recoveries for two compounds in rat blood were 87.9-109 %. The analytes were proved to be stable during all sample storage, preparation, and analytic procedures. The validated method was successfully applied to pharmacokinetic and PK/PD studies of SYL930 and SYL930-P in rats after oral administration of SYL930. Graphical Abstract Quantitative determination of SYL930 and its active phosphorylated metabolite in rat blood by LCMS/MS and application to PK/PD analysis.

Fragrance material review on 1-(para-menthen-6-yl)-1-propanone.

A toxicologic and dermatologic review of 1-(para-Menthen-6-yl)-1-propanone when used as a fragrance ingredient is presented. 1-(para-Menthen-6-yl)-1-propanone is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(para-Menthen-6-yl)-1-propanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, and skin sensitization, data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (2013) [Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013 A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones When Used as Fragrance Ingredients. Submitted with this manuscript.] for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances.

Two cases of acute propane/butane poisoning in prison.

Hydrocarbon inhalation is seldom chosen as a means to commit suicide. This practice is exclusively a prerogative of the prison population; it is, however, only exceptionally found in this environment. The two cases of lethal inhalation of propane/butane gas observed by us over a very short time occurred in this context. Toxicologic analyses were performed by means of gas chromatography (head space) and revealed a propane/butane mixture in all specimens (heart blood, bile, and urine) except vitreous humor. Although fatal arrhythmia posthydrocarbon gas abuse is well known, the concentrations of the two hydrocarbons were sufficient to induce death by asphyxiation and were distributed (fairly) homogeneously in all biological fluids and organs examined, a parameter permitting one to assume that death occurred within a relatively short period of time. The absence of finding in vitreous humor and the trace amount in urine suggests that both men died very quickly.

Quantification of a novel natural antioxidant (UP302) in rat plasma using ultra-high performance liquid chromatography-tandem mass spectrometry.

UP302 is a novel natural antioxidant isolated from Dianella ensifolia (Liliaceae). In the investigation, a specific and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry for quantitative determination of UP302 in rat plasma was developed and validated. UP302 and the internal standard daidzein were extracted from 100 µL aliquots of rat plasma using methanol. Detection of UP302 and IS was done by tandem mass spectrometry, operating in negative ion and selected reaction monitoring acquisition mode. The precursor-product ion transitions monitored for UP302 and daidzein were m/z 301.1→135.2 and 252.9→132.0, respectively. The linearity of the method was observed within the concentration range of 5-2000 ng/mL. Intra- and inter-day assay variations were less than 15%, and the accuracy values were between 99.2% and 107.3%. The method was successfully applied to stability investigation of UP302 incubated in rat plasma at 37°C and measurement of UP302 in plasma after intravenous administration of UP302 to rats at a single dose of 5 mg/kg. Incubation stability revealed that within first one hour, UP302 was rapidly declined approximately 35% and remained stable after 4 h. Pharmacokinetic values of half-life, volume of distribution, systemic clearance and mean residence time were 0.87 ± 0.58 h, 6.90 ± 3.35 L/kg, 5.89 ± 1.21 L/h kg and 0.34 ± 0.13 h, respectively.

Approaches to cancer assessment in EPA's Integrated Risk Information System.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program develops assessments of health effects that may result from chronic exposure to chemicals in the environment. The IRIS database contains more than 540 assessments. When supported by available data, IRIS assessments provide quantitative analyses of carcinogenic effects. Since publication of EPA's 2005 Guidelines for Carcinogen Risk Assessment, IRIS cancer assessments have implemented new approaches recommended in these guidelines and expanded the use of complex scientific methods to perform quantitative dose-response assessments. Two case studies of the application of the mode of action framework from the 2005 Cancer Guidelines are presented in this paper. The first is a case study of 1,2,3-trichloropropane, as an example of a chemical with a mutagenic mode of carcinogenic action thus warranting the application of age-dependent adjustment factors for early-life exposure; the second is a case study of ethylene glycol monobutyl ether, as an example of a chemical with a carcinogenic action consistent with a nonlinear extrapolation approach. The use of physiologically based pharmacokinetic (PBPK) modeling to quantify interindividual variability and account for human parameter uncertainty as part of a quantitative cancer assessment is illustrated using a case study involving probabilistic PBPK modeling for dichloromethane. We also discuss statistical issues in assessing trends and model fit for tumor dose-response data, analysis of the combined risk from multiple types of tumors, and application of life-table methods for using human data to derive cancer risk estimates. These issues reflect the complexity and challenges faced in assessing the carcinogenic risks from exposure to environmental chemicals, and provide a view of the current trends in IRIS carcinogenicity risk assessment.

Derivation of a reference dose and drinking water equivalent level for 1,2,3-trichloropropane.

In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100 ppb, resulting from past uses. In subchronic oral studies, TCP produced toxicity in kidneys, liver, and other tissues. TCP administered by corn oil gavage in chronic studies produced tumors at multiple sites in rats and mice; however, interpretation of these studies was impeded by substantial premature mortality. Drinking water equivalent levels (DWELs) were estimated for a lifetime of consumption by applying biologically-based safety/risk assessment approaches, including Monte Carlo techniques, and with consideration of kinetics and modes of action, to possibly replace default assumptions. Internationally recognized Frameworks for human relevance of animal data were employed to interpret the findings. Calculated were a reference dose (=39 microg/kg d) for non-cancer and Cancer Values (CV) (=10-14 microg/kg d) based on non-linear dose-response relationships for mutagenicity as a precursor of cancer. Lifetime Average Daily Intakes (LADI) are 3130 and 790-1120 microg/person-d for non-cancer and cancer, respectively. DWELs, estimated by applying a relative source contribution (RSC) of 50% to the LADIs, are 780 and 200-280 microg/L for non-cancer and cancer, respectively. These DWELs may inform establishment of formal/informal guidelines and standards to protect public health.

Comparative study on the in vitro human skin permeation of monoterpenes and phenylpropanoids applied in rose oil and in form of neat single compounds.

Essential oils are ingredients of cosmetic and health care products as well as massage oil used in aromatherapy. There is no doubt that essential oils and their components are able to permeate human skin. But information is rare dealing with percutanous absorption of essential oils in more detail. In this paper we investigated the in vitro skin permeation of monoterpenes and phenylpropanoids applied in pure rose oil and in form of neat single substances. We found that the application form had an exceeding influence on the skin permeation behaviour of the compounds. For substances applied in rose oil a clear relationship between their lipophilic character, chemical structure, and skin permeation could be confirmed. Regarding the P(app)-values the substances are ranked in the order: monoterpene hydrocarbons < monoterpene alcohols < monoterpene ketons < phenylpropanoids. In contrast, for neat single substances there were no relationships between their lipophilic characters, structures and skin permeation. Furthermore, except for alpha-pinene and isomenthone, the P(app)-values of all other substances were several times higher when applied in pure native rose oil than in their neat form. This suggests that co-operative interactions between essential oil components may promote skin permeation behaviour of essential oil and its components.

Metabolism of FPP-3, an anti-inflammatory propenone compound, in rat by liquid chromatography-electrospray ionization tandem mass spectrometry.

1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) is an anti-inflammatory agent with a propenone moiety. Following a single intravenous injection of male Sprague-Dawley rats with 4 mg/kg of FPP-3, three different metabolites of FPP-3 were identified as M1 (1-furan-2-yl-3-pyridin-2-yl-propan-1-one), M2 (1-furan-2-yl-3-pyridin-2-yl-propan-1-ol) and M3 (a glucuronide conjugate of M2) in rat urine by a liquid chromatography-electrospray tandem mass spectrometry. The structures of M1 and M2 were the same as observed previously following the incubation of rat liver microsomes with FPP-3 in the presence of NADPH. Although all metabolites of FPP-3 were identified in rat urine, only M1 and M2 were observed in the bile and feces. In addition, FPP-3 and its metabolites were mostly excreted into the urine. The M3 was identified as a glucuronide conjugate of M2 because of the addition of 176 Da from the protonated molecular ion of M2 in MS(2) and because of the production of free M2 following an incubation of urine with beta-glucuronidase. From these studies, a possible metabolic fate of FPP-3 could be proposed in vivo.

Identification of 1-furan-2-yl-3-pyridin-2-yl-propenone, an antiinflammatory agent, and its metabolites in rat liver subcellular fractions.

1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) has been characterized to have an anti-inflammatory activity through the inhibition of the production of nitric oxide and tumor necrosis factor-alpha. In the present studies, the phase 1 metabolism of FPP-3 was investigated in rat liver microsomes and cytosols. When FPP-3 was incubated with rat liver microsomes and cytosols in the presence of NADPH, 2 major peaks were detected on a liquid chromatography/electrospray ionization-mass spectrometry. Two metabolites (i.e., M1 and M2) were characterized as reduced forms on propenone: M1 (1-furan-2-yl-3-pyridin-2-yl-propan-1-one) was the initial metabolite and M2 (1-furan-2-yl-3-pyridin-2-yl-propan-l-ol) was a secondary alcohol believed to be formed from M1.

Determination of 1-furan-2-yl-3-pyridin-2-yl-propenone, an anti-inflammatory propenone compound, by high performance liquid chromatography with ultraviolet spectrometry.

1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) has recently been synthesized and characterized to have an anti-inflammatory activity. In the present study, pharmacokinetic parameters for FPP-3 and its metabolites were determined at the same time by using high-performance liquid chromatography-ultraviolet spectrometry. Two metabolites were detected in sera when FPP-3 was administered intravenously to male SD rats. The linearity of FPP-3, M1 (1-furan-2-yl-3-pyridin-2-yl-propan-1-one) and M2 (1-furan-2-yl-3-pyridin-2-yl-propan-1-ol) was confirmed in the concentration ranges of 0.5-20, 0.101-4.04 and 1.04-20.4 microg/ml, respectively. The lower limits of quantitation of FPP-3, M1 and M2 were 0.5, 0.1 and 1.0 microg/ml, respectively. The intra- and inter-day precision and accuracy over the concentration range of target compounds were within 13.5 and 14.2%, respectively. The half-lives of FPP-3, M1 and M2 were 16.3, 27.7 and 22.1 min, respectively.

Critical evaluation of the cancer risk of dibromochloropropane (DBCP).

Dibromochloropropane (1,2-dibromo-3-chloropropane, DBCP), a pesticide used widely for over 20 years to control nematodes on crops, turf and in nurseries, was banned by the United States Environmental Protection Agency (US EPA) in 1977 because of evidence of infertility in men and induction of a variety of tumors in laboratory animals. Despite the ban on the use of DBCP, this pesticide remains persistent in soil and continues to be detected as a groundwater contaminant in areas of past high use, in particular California's Central Valley. In this review, we present a critical evaluation of the available scientific literature on the potential for DBCP to affect cancer risk, including the results of animal cancer bioassays, human epidemiological studies and in vitro and in vivo genotoxicity studies. In addition, we provide updated information on DBCP chemistry and metabolism, production and past use, current regulations, its environmental fate, potential for human exposure and current remediation efforts. Results from long-term cancer bioassays in rodents show a statistically significant increase in the incidence of malignant and benign mammary gland tumors in female rats treated orally with DBCP compared to controls and some evidence of increased incidence of mammary fibroadenomas in DBCP low-dose treated female rats exposed by inhalation. Significantly increased incidence of tumors of the forestomach occurred in both sexes of rats and mice treated orally. Rats exposed to DBCP by inhalation showed significant increases in tumors of the tunica vaginalis in males; tumors of the pharynx and adrenal gland in females; and tumors of the tongue, nasal turbinate and nasal cavity in both sexes compared to controls. Male and female mice exposed to DBCP by inhalation experienced increased tumor incidence in the lungs and nasal cavity compared to controls. Significant increases in tumors of the lung and forestomach have also been reported in female mice treated by a dermal route. Although high mortality rates in both rat and mouse bioassays limited the ability to detect tumors late in life, the induction of a variety of tumors by multiple routes of exposure in two rodent species provides clear evidence of a DBCP tumorigenic response. In vitro, in vivo and human genotoxicity studies indicate that DBCP is capable of acting as a mutagen and clastogen. Few studies have been conducted to assess whether DBCP workplace or drinking water exposures affect cancer risk in humans. While case-control, cohort and ecological epidemiology studies have not found significant, positive associations between DBCP exposure and cancer in exposed populations, these studies have numerous limitations including small numbers of participants, a lack of control for confounding factors, lack of exposure information on DBCP and other chemicals and short follow-up times. Given the persistent nature of DBCP contamination in areas of past use, efforts should be made to continue remediation efforts and follow previously exposed populations for development of certain human cancers, including breast, ovarian, stomach, respiratory, oral and nasal cancers, among others.

Autoerotic accident by inhalation of propane-butane gas mixture.

We present a case of an accidental autoerotic death involving the inhalation of a propane-butane gas mixture, also known as LPG (liquefied petroleum gas). A 19-year-old male was found dead in supine position in his bed in a residential accommodation one day after he was last seen alive. On a personal computer at the end of the bed, a pornographic movie was still running. On his left shoulder, an empty rubber balloon and on the bedside 2 empty "Kisag-Gas" cartridges were found. Toxicologic investigations revealed an intoxication with propane and butane, together with a recent consumption of cannabis. This case report compares the toxicologic findings with other recently published cases, and the theories of the toxic effects are discussed.

[Fatal inhalation of butane-propane gas]. / Tödliche Inhalation von Butan-Propan-Gas.

Fatal intoxications with butane and/or propane are rare although the inhalation of such liquid gases in order to induce hallucinations is not uncommon amongst youngsters, the number of which is difficult to evaluate. Thus the possibility of gas intoxication should be taken into consideration in all cases of unclear death of youngsters, in which case the macroscopic and histological findings will be unspecific whereas the chemical-toxicological analyses, especially of the native brain, lung and liver tissue, lead to definite conclusions.

Haloalkane hydrolysis with an immobilized haloalkane dehalogenase.

Haloalkane dehalogenase from Rhodococcus rhodochrous was covalently immobilized onto a polyethyleneimine impregnated gamma-alumina support. The dehalogenating enzyme was found to retain greater than 40% of its original activity after immobilization, displaying an optimal loading (max. activity/supported protein) of 70 to 75 mg/g with an apparent maximum (max. protein/support) of 156 mg/g. The substrate, 1,2,3-trichloropropane, was found to favorably partition (adsorb) onto the inorganic alumina carrier (10 to 20 mg/g), thereby increasing the local reactant concentration with respect to the catalyst's environment, whereas the product, 2,3-dichloropropan-1-ol, demonstrated no affinity. Additionally, the inorganic alumina support exhibited no adverse effects because of solvent/component incompatibilities or deterioration due to pH variance (pH 7.0 to 10.5). As a result of the large surface area to volume ratio of the support matrix and the accessibility of the bound protein, the immobilized biocatalyst was not subject to internal mass transfer limitations. External diffusional restrictions could be eliminated with simple agitation (mixing speed: 50 rpm; flux: 4.22 cm/min). The pH-dependence of the immobilized dehalogenase was essentially the same as that for the native enzyme. Finally, both the thermostability and resistance toward inactivation by organic solvent were improved by more than an order of magnitude after immobilization.

Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to a genotoxicant.

The industrial solvent 2-nitropropane (2-NP) is a genotoxic hepatocarcinogen in rats. The genotoxicity of the compound in rats has been attributed to sulfotransferase-mediated formation of DNA-reactive nitrenium ions from the anionic form of 2-NP, propane 2-nitronate (P2N). Whether human sulfotransferases are capable of activating P2N is unknown. In the present study we have addressed this question by investigating the genotoxicity of P2N in various V79-derived cell lines engineered for expression of individual forms of human sulfotransferases, the phenol-sulfating and the monoamine-sulfating phenol sulfotransferases (hP-PST and hM-PST) and the human hydroxysteroid sulfotransferase (hHST). Genotoxicity was assessed by measuring the induction of DNA repair synthesis and by analyzing the formation of DNA modifications. P2N induced repair synthesis in V79-hP-PST and V79-hM-PST cells, whereas induction of repair synthesis in V79-hHST cells was negligible. P2N also resulted in the formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any sulfotransferase activity. Acetone oxime, the tautomeric form of the first reduction product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The results show that the human phenol sulfotransferases P-PST and M-PST are capable of metabolically activating P2N (P-PST >> M-PST) and that the underlying mechanism is apparently identical to that resulting in the activation of P2N in rat liver, where 2-NP causes carcinomas. These results support the notion that 2-NP should be regarded as a potential human carcinogen.