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<p>Polychlorinated biphenyls (PCBs) are globally distributed pollutants that continue to pose health risks for humans and wildlife. Many effects of PCBs differ between the non-ortho-substituted, dioxin-like (DL), and the ortho-substituted non-dioxin-like (NDL) congeners. Metabolism of PCB congeners by cytochrome P450 enzymes can strongly affect their toxicity. Here we report on metabolism of a NDL PCB congener, 2,2′,5,5′-tetrachlorobiphenyl (PCB52), by a P450 purified from the marine fish <i>Stenotomus chrysops</i> (scup). (Without sequence information this protein is necessarily referred to by its original name, scup P450B.) PCB52 was metabolized at rates from 0.2–2 pmol/min/mg of liver microsomal protein, correlated with immunodetected amounts of P450B, and antibodies to P450B inhibited PCB52 metabolism. We conclude that PCB52 is metabolized by scup P450B. The P450B N-terminal amino acid sequence shares identity with mammalian CYP2Bs. However, PCB52 is metabolized in mammals by CYP2As. Thus, scup P450B has properties of both mammalian CYP2A and CYP2B proteins. Comparative sequence analyses point to scup P450B being a fish CYP2Y. Notably zebrafish CYP2Y3 shares synteny with a cluster of CYP2 genes in mammals. Thus, catalytic function, sequence searching, and zebrafish synteny data lead us to conclude that scup P450B is a CYP2Y and a co-ortholog to genes in the mammalian CYP2ABFGST cluster.</p><p></p>

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Metabolism of 2,2′,5,5′-tetrachlorobiphenyl (PCB52) by a fish cytochrome P450 (CYP2Y) orthologous to the human CYP2ABFGST gene cluster

  • 期刊论文

  • 发表日期：

    2025年9月28日

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  • John J. Stegeman,
  • Renee D. White,
  • Hannah Agnes Knorr,
  • Jared V. Goldstone

摘要

Polychlorinated biphenyls (PCBs) are globally distributed pollutants that continue to pose health risks for humans and wildlife. Many effects of PCBs differ between the non-ortho-substituted, dioxin-like (DL), and the ortho-substituted non-dioxin-like (NDL) congeners. Metabolism of PCB congeners by cytochrome P450 enzymes can strongly affect their toxicity. Here we report on metabolism of a NDL PCB congener, 2,2′,5,5′-tetrachlorobiphenyl (PCB52), by a P450 purified from the marine fish Stenotomus chrysops (scup). (Without sequence information this protein is necessarily referred to by its original name, scup P450B.) PCB52 was metabolized at rates from 0.2–2 pmol/min/mg of liver microsomal protein, correlated with immunodetected amounts of P450B, and antibodies to P450B inhibited PCB52 metabolism. We conclude that PCB52 is metabolized by scup P450B. The P450B N-terminal amino acid sequence shares identity with mammalian CYP2Bs. However, PCB52 is metabolized in mammals by CYP2As. Thus, scup P450B has properties of both mammalian CYP2A and CYP2B proteins. Comparative sequence analyses point to scup P450B being a fish CYP2Y. Notably zebrafish CYP2Y3 shares synteny with a cluster of CYP2 genes in mammals. Thus, catalytic function, sequence searching, and zebrafish synteny data lead us to conclude that scup P450B is a CYP2Y and a co-ortholog to genes in the mammalian CYP2ABFGST cluster.