Stephanie L Born

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Coumarin is a known hepatotoxicant in laboratory animals, particularly rats. However, the mouse lung was identified as a major target organ in a chronic bioassay, with an oral gavage dosage of 200 mg/kg coumarin increasing the incidence of alveolar/bronchiolar adenomas and carcinomas. The purpose of the present work was to determine whether coumarin was(More)
Coumarin, a natural product and fragrance ingredient, is a well recognized rat liver toxicant, and dietary administration at toxic dosages increased the incidence of rat cholangiocarcinomas and parenchymal liver-cell tumors in a chronic bioassay. Hepatotoxicity in rats is site- and species-specific, and is thought to result from the formation of coumarin(More)
Coumarin, a widely used fragrance ingredient, is a rat liver and mouse lung toxicant. Species differences in toxicity are metabolism-dependent, with injury resulting from the cytochrome P450-mediated formation of coumarin 3,4-epoxide (CE). In this study, the enzymes responsible for coumarin activation in liver and lung were determined. Recombinant human and(More)
Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara cell death, resulted in a statistically significant increased incidence of alveolar/bronchiolar adenomas and carcinomas in(More)
Coumarin is used widely as a fragrance constituent and is administered clinically in the treatment of certain lymphedemas and malignancies. Although toxicity occurs only rarely in humans treated clinically with high-dose coumarin, it is well established that coumarin is hepatotoxic in the rat. This species difference in susceptibility to toxicity reflects(More)
o-Hydroxyphenylacetaldehyde (o-HPA), the product of coumarin 3, 4-epoxide, was synthesized and its contribution to the hepatotoxic effects of coumarin in the rat was determined. The relative toxicity of coumarin and o-HPA were initially assessed in Chinese hamster ovary K1 (CHO K1) cells, a cell line that does not contain cytochrome P450. In CHO K1 cells,(More)
Coumarin was identified as a mouse-lung carcinogen following oral gavage administration in a chronic bioassay, and was shown to cause the selective necrosis of terminal bronchiolar Clara (non-ciliated bronchiolar epithelial) cells in the mouse lung after acute administration. After oral gavage, a similar effect was not observed in the terminal bronchioles(More)
Coumarin-induced mouse Clara cell toxicity is thought to result from the local formation of coumarin 3,4-epoxide (CE). However, this toxicity is not observed in the rat, indicating species differences in coumarin metabolism. The purpose of the present work was to characterize the in vitro kinetics of coumarin metabolism in mouse, rat, and human whole lung(More)
Canine hepatic cytochrome P450 PBD-2 metabolizes 2,2',4,4',5,5'-hexachlorobiphenyl and catalyzes the 21-hydroxylation of progesterone, thereby distinguishing PBD-2 as unique among 2B P450s. Heterologous expression of the PBD-2 cDNA, P450 2B11, in COS and yeast systems produced a protein capable of androstenedione metabolism; however, this P450 did not(More)
High level Escherichia coli expression of cytochromes P450 3A12 and 3A6 has facilitated the characterization of proteins which exhibit limited activity as purified hepatic enzymes in reconstituted systems. Three 3A12 and two 3A6 constructs modified at the 5'-end to encode the bovine 17 alpha-sequence (Barnes et al., Proc. Natl. Acad. Sci. U.S.A. 88:(More)