We describe the first reported transmission to a human of simian foamy virus (SFV) from a free-ranging population of nonhuman primates in Asia. The transmission of an exogenous retrovirus, SFV, from macaques ( Macaca fascicularis ) to a human at a monkey temple in Bali, Indonesia, was investigated with molecular and serologic techniques. Antibodies to SFV were detected by Western blotting of serum from 1 of 82 humans tested. SFV DNA was detected by nested polymerase chain reaction (PCR) from the blood of the same person. Cloning and sequencing of PCR products confirmed the virus's close phylogenetic relationship to SFV isolated from macaques at the same temple. This study raises concerns that persons who work at or live around monkey temples are at risk for infection with SFV.

Hepatotoxicity of coumarin is attributed to metabolic activation to an epoxide intermediate, coumarin 3,4-epoxide (CE). However, whereas rats are most susceptible to coumarin-induced hepatotoxicity, formation of CE is greatest in mouse liver microsomes, a species showing little evidence of hepatotoxicity. Therefore, the present work was designed to test the hypothesis that detoxification of CE is a major determinant of coumarin hepatotoxicity. CE can either rearrange spontaneously to o-hydroxyphenylacetaldehyde (o-HPA) or be conjugated with gluatathione (GSH). o-HPA is hepatotoxic and is further detoxified by oxidation to o-hydroxyphenylacetic acid (o-HPAA). In vitro experiments were conducted using mouse liver microsomes to generate a constant amount of CE, and cytosols from F344 rats, B6C3F1 mice, and human liver were used to characterize CE detoxification. All metabolites were quantified by HPLC methods with UV detection. In rats and mice, GSH conjugation occurred non-enzymatically and through glutathione-S-transferases (GSTs), and the kinetics of GSH conjugation were similar in rats and mice. In rat liver cytosol, oxidation of o-HPA to o-HPAA was characterized with a high affinity K(m) of approximately 12 microM, and a V(max) of approximately 1.5 nmol/min/mg protein. In contrast, the K(m) and V(max) for o-HPA oxidation in mouse liver cytosol were approximately 1.7 microM and 5 nmol/min/mg protein, respectively, yielding a total intrinsic clearance through oxidation to o-HPAA that was 20 times higher in mouse than in rats. Human cytosols (two separate pools) detoxified CE through o-HPA oxidation with an apparent K(m) of 0.84 microM and a V(max) of 5.7 nmol/min/mg protein, for a net intrinsic clearance that was more than 50 times higher than the rat. All species also reduced o-HPA to o-hydroxyphenylethanol (o-HPE), but this was only a major reaction in rats. In the presence of a metabolic reaction replete with all necessary cofactors, GSH conjugation accounted for nearly half of all CE metabolites in rat and mouse, whereas the GSH conjugate represented only 10% of the metabolites in human cytosol. In mouse, o-HPAA represented the major ring-opened metabolite, accounting for the remaining 50% of metabolites, and in human cytosol, o-HPAA was the major metabolite, representing nearly 90% of all CE metabolites. In contrast, no o-HPAA was detected in rats, whereas o-HPE represented a major metabolite. Collectively, these in vitro data implicate o-HPA detoxification through oxidation to o-HPAA as the major determinant of species differences in coumarin-induced hepatotoxicity.

The purpose of the present experiments was to test the hypothesis that diethanolamine (DEA), an alkanolamine shown to be hepatocarcinogenic in mice, induces hepatic choline deficiency and to determine whether altered choline homeostasis was causally related to the carcinogenic outcome. To examine this hypothesis, the biochemical and histopathological changes in male B6C3F1 mice made choline deficient by dietary deprivation were first determined. Phosphocholine (PCho), the intracellular storage form of choline was severely depleted, decreasing to about 20% of control values with 2 weeks of dietary choline deficiency. Other metabolites, including choline, glycerophosphocholine (GPC), and phosphatidylcholine (PC) also decreased. Hepatic concentrations of S-adenosylmethionine (SAM) decreased, whereas levels of S-adenosylhomocysteine (SAH) increased. Despite these biochemical changes, fatty liver, which is often associated with choline deficiency, was not observed in the mice. The dose response, reversibility, and strain-dependence of the effects of DEA on choline metabolites were studied. B6C3F1 mice were dosed dermally with DEA (0, 10, 20, 40, 80, and 160 mg/kg) for 4 weeks (5 days/week). Control animals received either no treatment or dermal application of 95% ethanol (1.8 ml/kg). PCho was most sensitive to DEA treatment, decreasing at dosages of 20 mg/kg and higher and reaching a maximum 50% depletion at 160 mg/kg/day. GPC, choline, and PC also decreased in a dose-dependent manner. At 80 and 160 mg/kg/day, SAM levels decreased while SAH levels increased in liver. A no-observed effect level (NOEL) for DEA-induced changes in choline homeostasis was 10 mg/kg/day. Choline metabolites, SAM and SAH returned to control levels in mice dosed at 160 mg/kg for 4 weeks and allowed a 2-week recovery period prior to necropsy. In a manner similar to dietary choline deficiency, no fatty change was observed in the liver of DEA-treated mice. In C57BL/6 mice, DEA treatment (160 mg/kg) also decreased PCho concentrations, without affecting hepatic SAM levels, suggesting that strain-specific differences in intracellular methyl group regulation may influence carcinogenic outcome with DEA treatment. Finally, in addition to the direct effects of DEA on choline homeostasis, dermal application of 95% ethanol for 4 weeks decreased hepatic betaine levels, suggesting that the use of ethanol as a vehicle for dermal application of DEA may exacerbate or confound the biochemical actions of DEA alone. Collectively, the results demonstrate that DEA treatment causes a spectrum of biochemical changes consistent with choline deficiency in mice and demonstrate a clear dose concordance between DEA-induced choline deficiency and hepatocarcinogenic outcome.

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