Disposition and metabolism of cumene in F344 rats and B6C3F1 mice.

Cumene is a high-production volume chemical that has been shown to be a central nervous system depressant and has been implicated as a long-term exposure carcinogen in experimental animals. The absorption, distribution, metabolism, and excretion of [(14)C]cumene (isopropylbenzene) was studied in male rats and mice of both sexes after oral or intravenous administration. In both species and sexes, urine accounted for the majority of the excretion (typically ≥ 70%) by oral and intravenous administration. Enterohepatic circulation of cumene and/or its metabolites was indicated because 37% of the total dose was excreted in bile in bile duct-cannulated rats with little excreted in normal rats. The highest tissue (14)C levels in rats were observed in adipose tissue, liver, and kidney with no accumulation observed after repeat dosing up to 7 days. In contrast, mice contained the highest concentrations of (14)C at 24 h after dosing in the liver, kidney, and lung, with repeat dosing accumulation of (14)C observed in these tissues as well as in the blood, brain, heart, muscle, and spleen. The metabolites in the expired air, urine, bile, and microsomes were characterized with 16 metabolites identified. The volatile organics in the expired air comprised mainly cumene and up to 4% α-methylstyrene. The major urinary and biliary metabolite was 2-phenyl-2-propanol glucuronide, which corresponded with the main microsomal metabolite being 2-phenyl-2-propanol.

Structural Information from Hydrazine Radical Cation Optical Absorption Spectra.

Transition energies (E(op)) of the nitrogen-centered pi,pi absorption of tetraalkylhydrazine radical cations are quite sensitive to twist at the NN bond, nitrogen pyramidality, and mixing of the sigma orbitals with the pi system. Thirty-one examples for which E(op) varies from 63 to 107.5 kcal/mol are discussed with the aid of calculated values (E(calc)) for the 0,0 transition energy using simple (no configuration interaction) neutral-in-cation-geometry calculations on AM1-UHF geometry-optimized radical-cation structures. Significant changes in the difference between E(op) and E(calc) are observed for bis-N,N'-bicyclic systems, which are syn pyramidalized at nitrogen (twist angles near 0 degrees; E(op) about 23 kcal/mol larger than E(calc)) and for bis-N,N-bicyclic ones, which are anti pyramidalized (twist angles of 180 degrees; difference about 7 kcal/mol when calculations of 180 degrees structures are employed). Within these classes, changes in E(op) caused by changes in pyramidality and sigma,pi interaction are predicted well by the calculations. The tetraisopropylhydrazine radical cation has lambda(max) = 282 nm, but its tetracyclohexyl analogue shows two transitions, at 276 and 386 nm. This surprising difference is attributed to tetracyclohexylhydrazine radical cation having both untwisted and significantly twisted (estimated twist angle approximately 44 degrees ) forms occupied in solution, although the isopropyl compound only has the untwisted form significantly occupied.

Disposition of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5h)-furanone (mx) in b6c3f1 mice and f344 rats.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a mutagenic by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid glands. This study was designed to provide disposition/metabolism information in mice to evaluate the necessity of a National Toxicology Program chronic bioassay and to provide data for female rats. Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 h following oral administration of (14)C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 h postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid. Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.

Chemical and enzymatic oxidation of furosemide: formation of pyridinium salts.

Furosemide (Lasix) is frequently used in the treatment of cardiovascular and renal disease. Only one metabolite, furosemide glucuronide, has ever been identified. Oxidation of furosemide by cytochrome P450 has been demonstrated, but the metabolite(s) has never been identified. The oxidation of furosemide by dimethyldioxirane in acetone and by liver microsomal incubations was explored in this study. The first observable product from dimethyldioxirane oxidation was a ring-expanded enone resulting from an intramolecular condensation of the aldehyde group of the enonal, the secondary amine, and the carboxylic acid in a Mannich-like reaction. Keto-enol tautomerization and opening of the lactone gave a stable pyridinium salt. The pyridinium salt was also observed in the microsomal incubations of furosemide. The presence of an internal nucleophile in furosemide may have a significant effect on the toxicology and possibly the pharmacology of this furan.

Metabolism of furans in vitro: ipomeanine and 4-ipomeanol.

Ipomeanine (IPN), 4-ipomeanol (4-IPO), 1-ipomeanol (1-IPO), and 1,4-ipomeadiol (DIOL) are toxic 3-substituted furans found in mold-damaged sweet potatoes. IPN and 4-IPO are the most toxic, but all produce pulmonary toxicity in cattle and rodents, and 4-IPO induces hepatotoxicity in humans. These furans require metabolic activation to elicit toxicity, but the limited information obtained from previous metabolism studies prompted us to initiate the investigation reported here. Our initial studies of 4-IPO metabolism by rat liver microsomes demonstrated that the oxidation of 4-IPO to IPN and reduction to DIOL occurred and that more IPN was metabolized to a reactive species than 4-IPO or DIOL. Incubation of IPN and Gly produced a 2'-pyrrolin-5'-one adduct establishing that IPN was metabolized to an enedial. N-Acetylcysteine reacted with the 5'-aldehyde of the enedial to give two 2',5'-dihydro-2'-hydroxyfurans stabilized by H bonding between the 2'-OH and 3'-keto group. Reaction of the enedial metabolite of IPN with one GSH gave several adducts including a pyrrole derived from the 1,2-addition of GSH to the 5'-aldehyde as well as two tricyclic 2'-pyrrolines derived from the 1,4-addition of GSH at the 4'-position. The identities of the pyrrole and 2'-pyrroline GSH adducts were confirmed by observation of structurally similar adducts from Cys conjugation with the enedial metabolite of IPN. Several minor adducts from the conjugation of the enedial metabolite of IPN with two GSH were also detected. Mono-GSH and bis-GSH adducts were derived from both the 1,2-and 1,4-addition of GSH to the enedial metabolite of 4-IPO in rat liver microsomal incubations of 4-IPO and GSH. Sequential oxidation of 4-IPO to IPN and then to the enedial metabolite followed by GSH conjugation also occurred in the 4-IPO incubations. The complex structures of the reaction products of the enedial with biological nucleophiles may explain why the many attempts to identify 4-IPO adducts to protein have not been successful.