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The present study examined whether modified xenobiotic transport, resulting from chlordecone (CD) or dieldrin pretreatment, would alter polycyclic aromatic hydrocarbon (PAH) or organochlorine (OC) target organ doses and subsequent tumor organospecificity or incidence rates in rainbow trout. Additionally, the potential for exposure to dieldrin or CD, following PAH exposure, to enhance tumor incidence was assessed. Evaluation of CD pretreatment effects on \[14C]CD disposition in trout was conducted following two ip (0-15 mg/kg) and two dietary (0-0.4 mg/kg/d) pretreatment regimes. To assess the influence of OC pretreatment on cancer induced by the PAH 7,12-dimethylbenz\[a]anthracene (DMBA), juvenile trout were fed control, CD (0.1, 0.4 mg/kg/d), or dieldrin (0.1, 0.3 mg/kg/d) diets for 9 wk, received a waterborne \[3H]DMBA exposure (1 mg/L, 20 h), and resumed control, CD, or dieldrin diets for 33 wk. \[3H]DMBA disposition and hepatic \[3H]DMBA binding were examined immediately and 24 h after exposure. Hepatic and stomach tumor incidences were determined 33 wk after DMBA exposure. CD pretreatment did not influence \[14C]CD or \[3H]DMBA hepatic concentrations, hepatic \[3H]DMBA DNA binding, or hepatic/stomach tumor incidence. It did, however, elevate bile \[14C]CD and \[3H]DMBA concentrations. Postinititation exposure to CD weakly enhanced DMBA-induced hepatic tumor incidence at the low but not the high CD dose. Dieldrin pretreatment did not influence stomach \[3H]DMBA equivalents or stomach tumor incidence but did cause an elevation in biliary and hepatic concentrations of \[3H]DMBA equivalents. \[3H]DMBA binding to liver DNA was significantly increased and hepatic tumor incidence was elevated by dieldrin pretreatment. Dieldrin treatment following DMBA initiation did not enhance hepatic or stomach tumor incidence. Ecoepidemiology studies, to date, have reported correlations between the co-occurrence of PAHs and OCs and elevated tumor incidence in feral fish, but cause-and-effect relationships have been difficult to establish. The results of the present study confirm that OCs, such as dieldrin and CD, play a role in modifying PAH-induced carcinogenesis in fish. [ABSTRACT FROM AUTHOR]

Pretreatment of mice with chlordecone (CD) reduced hepatic accumulation of a subsequent dose of [14C]CD without significantly changing [14C]CD biotransformation. To determine if CD-induced changes in hepatic [14C]CD accumulation were coincident with altered cell composition, we examined the effects of CD on hepatic protein and lipid content, on fatty acid profiles of liver and kidney, and on the ultrastructure of hepatocytes. SDS-polyacrylamide gel electrophoresis detected an apparent CD dose-related increase in a microsomal protein with a molecular weight of about 23 kDa. Total liver or kidney lipid contents were not altered by CD but relative amounts of several hepatic fatty acids were changed. CD caused marked hepatic mitochondrial swelling, increased amounts of endoplasmic reticulum, apparently increased numbers of peroxisome-like structures, and decreased numbers of lipid droplets in cytoplasm of hepatocytes. Numbers of lipid droplets were not decreased in perisinusoidal fat storage cells. In addition, the numbers of cytoplasmic lipoprotein vesicles were apparently increased in some hepatocytes. Overall these changes indicated an increased hepatocyte secretory activity and suggested that CD changed hepatocellular lipid transport, storage, and metabolism pathways. [ABSTRACT FROM PUBLISHER]

We previously demonstrated that pretreatment of rainbow trout with the organochlorine insecticide dieldrin altered in vivo disposition of a subsequent [14C]dieldrin dose. This was not explained by changes in total lipid content or the activity of common xenobiotic metabolizing enzymes. We hypothesized that dieldrin induced hepatic proteins responsible for organochlorine (OC) sequestration, transport, or excretion and that these changes reflected an adaptive response of trout to OC exposure. Here, uptake of 1.18 μM [14C]-dieldrin by precision cut liver slices was increased by dieldrin pretreatment of rainbow trout. Uptake of 0.118 and 1.18 μM [3H]-7,12-dimethylbenz[a]anthracene (DMBA) and efflux of 0.118 μM [3H]DMBA were significantly increased in slices from dieldrin pretreated trout. Liver slice uptake of 10 but not 1.18 μM [3H] estradiol and [3H]cholic acid was significantly increased by dieldrin pretreatment. There were no such significant differences for [3H]cholesterol, or [3H]cholesterol-oleate, or [3H]oleic acid uptake. Dieldrin pretreatment did not alter hepatic microsomal metabolism of [3H]DMBA or [14C]benzo[a]pyrene or content of six cytochrome P450 isozymes, as quantitated by Western blot analysis. These results provide further evidence that altered disposition of [14C]dieldrin and [3H]DMBA in dieldrin-pretreated trout was not explained by microsomal enzyme induction but reflected altered processes integral to hepatocellular transmembrane kinetics. These changes may have important implications for OC bioaccumulation by rainbow trout and demonstrate an interaction between dieldrin and DMBA in the absence of cytochrome P450 system induction. [ABSTRACT FROM AUTHOR]

Previous work demonstrated that exposure of laboratory animals including fish to certain organochlorine (OC) insecticides altered the tissue distribution of a subsequent tracer dose of the same [C]OC. In the present study, 10- to 20-g rainbow trout were exposed to 15 ppm dieldrin in the diet. Fish were subsequently challenged at 2-week intervals with an intraperitoneal injection of 0.1 mg/kg [C]dieldrin and viscera (liver, bile, mesenteric fat, kidney, and intestine) analyzed for radioactivity 24 hr later. After 10 and 12 weeks of dieldrin pretreatment, [C]-dieldrin was significantly elevated relative to controls in liver (200%), bile (500%), and fat (500 and 1200% for 10 and 12 weeks, respectively) of pretreated fish. Other tissues were unchanged. Chloroform/methanol extractions revealed a time-dependent increase in label disposition to carcass lipid in controls but not in pretreated fish. Altered disposition could not be explained by changes in total body lipid or induction of total cytochrome P-450 or ethoxyresorufin--deethylase, pentoxyreso-rufin--deethylase, glutathione -transferase, or UDP glucuronosyltransferase activities. assessment of [C]dieldrin metabolism revealed no increase in hepatic and only a slight (22%) increase in biliary polannonpolar concentration ratio after 9 weeks 20 ppm dieldrin pretreatment. Results suggest that constitutive changes in liver integral to dieldrin sequestration, transport, or excretion may be an adaptive response of trout to chronic OC exposure. [ABSTRACT FROM PUBLISHER]

Previous work identified two common ethnically-dependent allelic variants of human flavin-containing monooxygenase 2 (FMO2) that encode protein with monooxygenase activity that could occur in combination with the functional FM02*1 allele (Q472 protein); the encoded proteins were S195L and N413K. To understand how these variants alter enzyme activity, we performed assays with the FMO substrate, methyl p-tolyl sulfide (MTS) under a range of conditions with S195L, N413K and Q472 produced by over-expression in Sf9 insect cells. MTS sulfoxidation was assayed by HPLC. All protein variants demonstrated the same pattern of response to the presence of magnesium (increased activity) and to heat (decreased activity). Increased activity was observed with Q472 and N413K in response to increasing pH and to cholate, while S195L had diminished activity. The major effect of the N413K substitution was to increase velocity compared with Q472, while S195L had reduced activity and altered patterns of response to incubation conditions. In contrast to Q472 and N413K, S195L activity was negligible unless NADPH was added before MTS. Also, the K,, for S195L is at least 10-fold higher than for Q472 and N413K. Although these allelic variants are expected to occur infrequently as mutations to the FM02*1 allele, they contribute to our overall understanding of mammalian FMO structure and function. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (BaP) is formed by incomplete combustion of organic materials (petroleum, coal, tobacco, etc.). BaP is designated by the International Agency for Research on Cancer as a group 1 known human carcinogen; a classification supported by numerous studies in preclinical models and epidemiology studies of exposed populations. Risk assessment relies on toxicokinetic and cancer studies in rodents at doses 5-6 orders of magnitude greater than average human uptake. Using a dose-response design at environmentally relevant concentrations, this study follows uptake, metabolism, and elimination of [ 14 C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250 ng (2.7-27 nCi) of [ 14 C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [ 14 C]-BaP and metabolites in plasma measured over 48 h. [ 14 C]-BaP median T max was 30 min with C max and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250 ng dose was seen with 7 volunteers as measured by the C max (8.99 ± 7.08 ng × mL -1 ) and AUC 0-48hr (68.6 ± 64.0 fg × hr -1  × mL -1 ). Approximately 3-6% of the [ 14 C] recovered (AUC 0-48 hr ) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30 min), a substantial percentage of [ 14 C] in plasma was polar BaP metabolites. The best fit modeling approach identified non-compartmental apparent volume of distribution of BaP as significantly increasing as a function of dose (p = 0.004). Bay region tetrols and dihydrodiols predominated, suggesting not only was there extensive first pass metabolism but also potentially bioactivation. AMS enables the study of environmental carcinogens in humans with de minimus risk, allowing for important testing and validation of physiologically based pharmacokinetic models derived from animal data, risk assessment, and the interpretation of data from high-risk occupationally exposed populations., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although all forms of vitamin E are absorbed, the liver preferentially secretes alpha-, but not gamma-tocopherol, into plasma. Liver alpha-tocopherol secretion is under the control of the alpha-tocopherol transfer protein (TTP). Therefore, to assess gamma-tocopherol bioactivities Ttpa-/-, +/- and +/+ mice were fed for 5 weeks diets containing gamma-tocopherol 550 (gamma-T550), gamma-tocopherol 60 (gamma-T60) mg/kg that also contained trace amounts of alpha-tocopherol, a vitamin E-deficient diet, or a control diet. Plasma and tissues from mice fed gamma-T550 diets were found to contain similar gamma- and alpha-tocopherol concentrations despite the high dietary gamma-tocopherol content; nervous tissues contained almost no gamma-tocopherol. Liver vitamin E metabolites (carboxyethyl hydroxychromans, CEHCs) were also measured. In mice with widely ranging liver alpha- (from 0.7 to 16 nmol/g) and gamma-tocopherol concentrations (0 to 13 nmol/g), hepatic alpha-CEHC was undetectable, but gamma-CEHC concentrations (0.1 to 0.8 nmol/g) were correlated with both alpha- and gamma-tocopherol concentrations (P < 0.004). Hepatic cytochrome P450s (CYPs) involved in vitamin E metabolism, Cyp4f and Cyp3a, were also measured. There were no variations in Cyp4f protein expression as related to diet or mouse genotype. However, Cyp3a was correlated (P < 0.0001) with liver alpha-, but not gamma-tocopherol concentrations. These data support the hypothesis that alpha-tocopherol modulates xenobiotic metabolism by increasing Cyp3a expression, gamma-CEHC formation, and the excretion of both gamma-tocopherol and gamma-CEHC.