CYP1A in TCDD Toxicity and in Physiology–with Particular Reference to CYP Dependent Arachidonic Acid Metabolism and other Endogenous Substrates

Abstract

Toxicologic and physiologic roles of CYP1A enzyme induction, the major biochemical effect of aryl hydrocarbon receptor activation by TCDD and other receptor ligands, are unknown. Evidence is presented that CYP1A exerts biologic effects via metabolism of endogenous substrates (i.e., arachidonic acid, other eicosanoids, estrogens, bilirubin, and melatonin), production of reactive oxygen, and effects on K⁺ and Ca²⁺ channels. These interrelated pathways may connect CYP1A induction to TCDD toxicities, including cardiotoxicity, vascular dysfunction, and wasting. They may also underlie homeostatic roles for CYP1A, especially when transiently induced by common chemical exposures and environmental conditions (i.e., tryptophan photoproducts, dietary indoles, and changes in oxygen tension).

Key Words :

• CYP1A1
• CYP1A2
• CYP1A4
• CYP1A5
• EETs
• 20-HETE
• TCDD
• Ah receptor
• Arachidonic acid
• Potassium ion channels
• Calcium ion channels
• Toxicity
• Physiology
• Endogenous substrates

Notes

¹The availability of an easy, sensitive, fluorescent assay with high selectivity for CYP1A1, 7-ethoxyresorufin deethylase (EROD), has facilitated studies of CYP1A1. Studies of CYP1A2 have not advanced as rapidly, in part because there is no comparable assay for CYP1A2. Methoxyresorufin has been suggested to be a CYP1A2 selective substrate and is commonly used for that purpose. However, although methoxyresorufin demethylase seems to reflect CYP1A preferentially (Weaver et al., 1994) it does not have the requisite selectivity for CYP1A2 to be used reliably across species, as an index of CYP1A2 (Burke et al., 1994; Hamm et al., 1998). The development of a fluorescence assay comparable to EROD with good CYP1A2 selectivity across species would advance understanding of CYP1A2 regulation and function.

²It would be more informative to have 20-HETE separated from other “terminal HETEs” (16–19 HETE), but this distinction is not always made, particularly in the earlier studies.