No abstract

During the 1992 breeding season, eggs of bald eagles (Haliaeetus leucocephalus) were collected within a gradient of exposure to chlorinated hydrocarbon pollutants, particularly from pulp mill point sources, on the southern coast of British Columbia, Canada. Twenty-five eggs were placed in a laboratory incubator, of which 18 hatched; chicks were sacrificed within 24 h. Hatching success was not significantly different between eggs taken from pulp mill sites and reference sites. A hepatic cytochrome P4501A (CYP1A) cross-reactive protein was induced nearly sixfold in chicks from near a pulp mill at Powell River compared to those from a reference site (p Ͻ 0.05). Hepatic ethoxyresorufin-O-deethylase (EROD) and benzyloxyresorufin O-dealkylase (BROD) activities were also significantly elevated in chicks from nests located near pulp mills compared to reference sites (p Ͻ 0.0005 and p Ͻ 0.02, respectively). A hepatic CYP2B cross-reactive protein was threefold higher in chicks from pulp mill versus reference sites, but the difference was not significant. Residual yolk sacs of eggs collected near pulp mill sites contained greater concentrations of 2,3,7,8substituted polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) compared to reference areas. No significant differences in concentrations of polychlorinated biphenyls (PCBs), non-ortho congeners, and organochlorine pesticides occurred among sites. Regressions showed that the hepatic CYP1A cross-reactive protein and EROD and BROD activities were positively correlated with 2,3,7,8-TCDD, 2,3,7,8-TCDF, and toxic equivalents (TEQs WHO -World Health Organization toxic equivalence factors) in yolk sacs. No significant concentration-related effects were found for morphological, physiological, or histological parameters, such as chick growth, edema, or density of thymic lymphocytes. Using hepatic CYP1A induction as a biomarker, a no-observedeffect-level (NOEL) of 100 ng/kg and a lowest-observed-effect-level (LOEL) of 210 ng/kg TEQs WHO on a whole egg (wet weight basis) are suggested for bald eagle chicks. Keywords-Bald eagleEmbryotoxicity TCDD Non-ortho PCBs P450Chlorinated hydrocarbon effects on bald eagles Environ. Toxicol. Chem. 15, 1996 783 Environ. Toxicol. Chem. 15, 1996 J.E. Elliott et al. Environ. Toxicol. Chem. 15, 1996 J.E. Elliott et al.Council of Canada. This project was part of a Ph.D. project on toxicology of chlorinated hydrocarbons in British Columbia bald eagles.

No abstract

Abstract-During the 1992 breeding season, eggs of bald eagles (Haliaeetus leucocephalus) were collected within a gradient of exposure to chlorinated hydrocarbon pollutants, particularly from pulp mill point sources, on the southern coast of British Columbia, Canada. Twenty-five eggs were placed in a laboratory incubator, of which 18 hatched; chicks were sacrificed within 24 h. Hatching success was not significantly different between eggs taken from pulp mill sites and reference sites. A hepatic cytochrome P4501A (CYP1A) cross-reactive protein was induced nearly sixfold in chicks from near a pulp mill at Powell River compared to those from a reference site (p Ͻ 0.05). Hepatic ethoxyresorufin-O-deethylase (EROD) and benzyloxyresorufin O-dealkylase (BROD) activities were also significantly elevated in chicks from nests located near pulp mills compared to reference sites (p Ͻ 0.0005 and p Ͻ 0.02, respectively). A hepatic CYP2B cross-reactive protein was threefold higher in chicks from pulp mill versus reference sites, but the difference was not significant. Residual yolk sacs of eggs collected near pulp mill sites contained greater concentrations of 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) compared to reference areas. No significant differences in concentrations of polychlorinated biphenyls (PCBs), non-ortho congeners, and organochlorine pesticides occurred among sites. Regressions showed that the hepatic CYP1A cross-reactive protein and EROD and BROD activities were positively correlated with 2,3,7,8-TCDD, 2,3,7,8-TCDF, and toxic equivalents (TEQs WHO -World Health Organization toxic equivalence factors) in yolk sacs. No significant concentration-related effects were found for morphological, physiological, or histological parameters, such as chick growth, edema, or density of thymic lymphocytes. Using hepatic CYP1A induction as a biomarker, a no-observedeffect-level (NOEL) of 100 ng/kg and a lowest-observed-effect-level (LOEL) of 210 ng/kg TEQs WHO on a whole egg (wet weight basis) are suggested for bald eagle chicks.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Clinically, cimetidine therapy impairs the clearance of various drugs metabolized by CYP2D6, such as desipramine and sparteine. Cimetidine is known to reversibly inhibit CYP2D6 in vitro; however, K i values are greater than plasma concentrations observed in vivo. There is evidence suggesting that this drug may act as an inactivator of cytochrome P450 (P450) enzymes after metabolic activation. Therefore, the purpose of this study was to determine whether cimetidine acts as a mechanism-based inactivator of CYP2D6. Dextromethorphan O-demethylation was used as a probe of CYP2D6 activity. The V max and K m of this reaction were 0.82 ؎ 0.06 nmol/min/nmol of P450 and 4.1 ؎ 0.1 M, respectively, in pooled human liver microsomes; and 15.9 ؎ 0.8 nmol/min/nmol P450 and 1.4 ؎ 0.6 M, respectively, with recombinant CYP2D6.With human liver microsomes, cimetidine competitively inhibited CYP2D6 (K i ‫؍‬ 38 ؎ 5 M) and was a mixed inhibitor of recombinant CYP2D6 (K i ‫؍‬ 103 ؎ 17 M). Preincubation of human liver microsomes with cimetidine and NADPH did not increase the inhibitory potency of cimetidine; however, preincubation with recombinant CYP2D6 resulted in enzyme inactivation that could be attenuated by the CYP2D6 inhibitor quinidine. The K I and k inact were estimated to be 77 M and 0.03 min ؊1 , respectively, and the half-life of inactivation was 25 min. Therefore, cimetidine may represent a class of compounds capable of inactivating specific cytochromes P450 in vivo, but for which conditions may not be achievable in vitro using human liver microsomes.