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Biotransformation of Polycyclic Aromatic Hydrocarbons by Trout Liver S9 Fractions: Evaluation of Competitive Inhibition Using a Substrate Depletion Approach.

ABSTRACT: Environmental contaminants frequently occur as part of a chemical mixture, potentially resulting in competitive inhibition among multiple substrates metabolized by the same enzyme. Trout liver S9 fractions were used to evaluate the biotransformation of 3 polycyclic aromatic hydrocarbons (PAHs): phenanthrene, pyrene, and benzo[a]pyrene, tested as binary mixtures. Initial rates of biotransformation were determined using a substrate-depletion approach. The resulting data were then fitted by simultaneous nonlinear regression to a competitive inhibition model. In each case, the PAH possessing the lower Michaelis-Menten affinity constant (K_M ) competitively inhibited biotransformation of the other compound. Inhibition constants determined for the lower-K_M compound were generally close to previously determined K_M values, consistent with the suggestion that phase I biotransformation of PAHs is largely catalyzed by one or a small number of cytochrome P450 enzymes. The use of a substrate-depletion approach to perform enzyme-inhibition studies imposes practical limitations on experimental design and complicates the interpretation of derived kinetic constants. Nevertheless, the resulting information may have utility for chemical hazard assessments as well as the design and interpretation of controlled laboratory studies. Depletion experiments informed by measured chemical concentrations in tissues may also provide a means of determining whether enzyme inhibition occurs under relevant environmental conditions. Environ Toxicol Chem 2019;38:2729-2739. Published 2019 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work, and as such, is in the public domain in the United States of America.

SUBMITTER: Nichols JW

PROVIDER: S-EPMC6952120 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Biotransformation of Polycyclic Aromatic Hydrocarbons by Trout Liver S9 Fractions: Evaluation of Competitive Inhibition Using a Substrate Depletion Approach.

Nichols John W JW Ladd Melanie A MA Hoffman Alex D AD Fitzsimmons Patrick N PN

Environmental toxicology and chemistry 20191105 12

Environmental contaminants frequently occur as part of a chemical mixture, potentially resulting in competitive inhibition among multiple substrates metabolized by the same enzyme. Trout liver S9 fractions were used to evaluate the biotransformation of 3 polycyclic aromatic hydrocarbons (PAHs): phenanthrene, pyrene, and benzo[a]pyrene, tested as binary mixtures. Initial rates of biotransformation were determined using a substrate-depletion approach. The resulting data were then fitted by simulta ...[more]

PMID: 31505707

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Project description:Biotransformation may substantially reduce the extent to which organic environmental contaminants accumulate in fish. Presently, however, relatively little is known regarding the biotransformation of ionized chemicals, including cationic surfactants, in aquatic organisms. To address this deficiency, a rainbow trout liver S9 substrate depletion assay (RT-S9) was used to measure in vitro intrinsic clearance rates (CLint ; ml min-1 g liver-1 ) for 22 cationic surfactants that differ with respect to alkyl chain length and degree of methylation on the charged nitrogen atom. None of the quaternary N,N,N-trimethylalkylammonium compounds exhibited significant clearance. Rapid clearance was observed for N,N-dimethylalkylamines, and slower rates of clearance were measured for N-methylalkylamine analogs. Clearance rates for primary alkylamines were generally close to or below detectable levels. For the N-methylalkylamines and N,N-dimethylalkylamines, the highest CLint values were measured for C10 -C12 homologs; substantially lower clearance rates were observed for homologs containing shorter or longer carbon chains. Based on its cofactor dependency, biotransformation of C12 -N,N-dimethylamine appears to involve one or more cytochrome P450-dependent reaction pathways, and sulfonation. On a molar basis, N-demethylation metabolites accounted for up to 25% of the N,N-dimethylalkylamines removed during the 2-h assay, and up to 55% of the removed N-methylalkylamines. These N-demethylation products possess greater metabolic stability in the RT-S9 assay than the parent structures from which they derive and may contribute to the overall risk of ionizable alkylamines. The results of these studies provide a set of consistently determined CLint values that may be extrapolated to whole trout to inform in silico bioaccumulation assessments. Environ Toxicol Chem 2021;40:3123-3136. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Dataset Information

Biotransformation of Polycyclic Aromatic Hydrocarbons by Trout Liver S9 Fractions: Evaluation of Competitive Inhibition Using a Substrate Depletion Approach.

Publications

Biotransformation of Polycyclic Aromatic Hydrocarbons by Trout Liver S9 Fractions: Evaluation of Competitive Inhibition Using a Substrate Depletion Approach.

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