Sterigmatocystin (ST), a potent hepatocarcinogen, was covalently bound to calf thymus DNA by incubation in the presence of phenobarbital-induced rat liver microsomes. Acid hydrolysis of ST-modified DNA liberated a major guanine-containing adduct, present in DNA at an estimated level of 1 ST residue per 100-150 nucleotides. The adduct was isolated by high-pressure liquid chromatography and subjected to structural analysis. Spectral and chemical data identified the adduct as 1dihydro-2(NI-guanyl)--hydroxysterigmatocystin, the guanine and hydroxyl moieties being in a trans configuration. The structure and stereochemistry of this adduct indicated that the exo-ST-1,2-oxide was the metabolite that reacted with DNA, and the quantitative yield of adduct indicated that this metabolite was a major product of the in vitro metabolism of ST.Sterigmatocystin 'ST) is a carcinogenic mycotoxin produced as a secondary metabolite by Aspergillus, Penicillium, and Bipolaris species (1, 2). ST is acutely toxic to the liver of most animals tested (3, 4), and its carcinogenicity has been demonstrated with organ specificity varying with species and route and frequency of administration (5-9). In rats, ST induces hepatocellular carcinomas after oral administration (6) or intraperitoneal injection (5) and squamous cell carcinomas after repeated application to the skin (7). Despite its potent toxic and carcinogenic properties in animals, the importance of ST as a human health hazard is unknown because surveillance programs have detected its presence in foods only infrequently and at low concentrations even though ST-producing fungi are widely distributed (10).Nonetheless, ST is of interest as a model compound for cancer induction because of its structural similarity to aflatoxin B1 (AFB1). In rats and monkeys, the lethal potency of ST is about 1/10th that of AFB1 (3), and ST is between 1 and 2 orders of magnitude less potent as a hepatocarcinogen for the rat (5, 6). A comparable quantitative difference exists in the toxicities and mutagenicities of ST and AFB1 in Salmonella typhimurium (11,12).In contrast to the large literature on AFB1, little information has been published on the metabolism and biochemical effects of ST. It has been shown that a large portion of the dose administered to monkeys is converted to a ST-glucuronide (13) and that metabolic activation is required for the toxicity and mutagenicity of ST in bacteria and some cultured cells (11,12,(14)(15)(16). Mammalian cells in culture exposed to ST display nucleolar aberrations, inhibited mitosis, inhibited uptake of thymidine and uridine, and stimulated DNA repair synthesis (17)(18)(19)(20). ST also has been demonstrated to inhibit RNA synthesis in rat liver (21) (N7-guanyl)-l-hydroxysterigmatocystin (ST-N7-Gua). § MATERIALS AND METHODSST was metabolically activated in the presence of calf thymus DNA by using phenobarbital-induced rat liver microsomes. The incubation mixture (400 ml; divided into eight 50-ml portions) included approximately 1 mg of microsomal protein...

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The objective of our research was to measure accurate rate constants for the thermal, unimolecular decomposition of organic nitrates. Our research confirms that the rate-determining step is homolytic cleavage of the weak O-N bond to form alkoxy radical and NO 2 , but the rate constants reported in the past are incorrect. The alkoxy radical and NO 2 engage in secondary reactions that ultimately generate stable products such as carbonyl and nitro compounds. Infrared spectroscopy (IR) and gas chromatography/mass spectrometry (GC/MS) were used to monitor the time dependent loss of organic nitrate and to characterize the products of the thermal reaction. Past research indicates that oxygen slows the rate of homolytic O-N bond cleavage to form radicals. Our research shows that the rates are the same in nitrogen as they are in air. The reaction in air produces R-β unsaturated ketones/aldehydes, which are not generated in a nitrogen atmosphere. The unsaturated ketone/aldehydes complicate the IR analysis, giving the appearance that the loss of organic nitrate slows down. Unhindered, linear organic nitrates have lower reaction rate constants than hindered organic nitrates. Activation energies were found to be lower for hindered organic nitrates. The steric strain present in the hindered organic nitrates may account for the weaker O-N bonds and faster thermal reaction rates. Reaction rates for thermal decomposition under nitrogen were found to decrease as the viscosity of the solvent increased.

This study summarizes the synthesis of model compounds. Long-chain alkyl multi-ring heteroaromatics are the synthetic targets. These compounds are considered analogues of similar compounds that are present at abundant levels in petroleum crude oils, resids, heavy oils, deasphalted oils, asphaltenes, and bitumens, and they are responsible for coke formation and other processing problems. Model compounds are not readily available. Some models have been synthesized to approximate the physical and chemical behavior of real asphaltenes, but the structures are not completely consistent with the current structural understanding. The composition of petroleum crudes, resids, heavy oils, and bitumens has been a subject of intense research for years. The structure of these coke-forming molecules is generally thought to be an aromatic core of critical molecular weight and number of fused aromatic rings. This critical ring number is around 4À5 fused aromatic rings, which bear alkyl side chains and heteroatoms. This general structural view is still being improved. During coking, these side chains thermally cleave off of the aromatic core and leave the coker as volatile liquids and gas. The aromatic cores are thermally stable, and they are not volatile. They remain in the coker until they condense and form low-value coke. The purpose of this research was to synthesize model compounds representing the molecular structure of the coke-forming molecules. These compounds will be used to model the behavior of resids, heavy oils, and bitumens to understand their processing chemistry and their physical and chemical properties. Model compounds that reasonably represent the structural data with boiling point ranges that map directly onto the boiling point ranges of real heavy oils, resids, and bitumens have been successfully synthesized. Important structural features are emphasized in these models, such as high molecular weight [∼1000 atomic mass units (amu)] with multi-ring aromatic cores, long alkyl side chains, and the inclusion of sulfur and nitrogen. These model compounds can be used to calibrate analytical methods to provide response factors for quantitative characterization of alkylated aromatics in real petroleum fractions and to better understand thermal chemistry kinetics.