Role in development In terms of evolution, the oldest physiological role of AhR is in development. AhR is presumed to have evolved from
invertebrates where it served a ligand-independent role in normal development processes. The AhR homolog in
Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg.
Ss dimerizes with
tango (tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription.
Evolution of the receptor in
vertebrates resulted in the ability to bind ligands and might have helped humans evolve to tolerate smoky fires. In developing vertebrates, AhR seemingly plays a role in cellular proliferation and differentiation. Despite lacking a clear endogenous ligand, AhR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis, lymphoid systems, T-cells, neurons, and hepatocytes. AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion and is involved in megakaryocyte differentiation. In adulthood, signaling is associated with the stress response and mutations in AhR are associated with major depressive disorder.
Adaptive and innate response The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the AhR signaling pathway. The search for other metabolizing genes induced by AhR ligands, due to the presence of DREs, has led to the identification of an "AhR gene battery" of Phase I and Phase II metabolizing enzymes consisting of
CYP1A1,
CYP1A2,
CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1. Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates AhR is able to bind and facilitate their
biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods. AhR activation seems to be also important for immunological responses and inhibiting inflammation and downregulation of
Th17 response. The Knockdown of AHR mostly downregulates the expression of innate immunity genes in
THP-1 cells.
Toxic response Extensions of the adaptive response are the toxic responses elicited by AhR activation. Toxicity results from two different ways of AhR signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon benzo(a)pyrene|benzo[
a]pyrene (BaP), a ligand for AhR, induces its own metabolism and bioactivation to a toxic metabolite via the induction of
CYP1A1 and
CYP1B1 in several tissues. The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "AhR gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.
Microarray analysis has proved most beneficial in understanding and characterizing this response. Xenobiotic metabolizing enzymes help with the metabolic process by transforming and the excretion of chemicals. The most potent inducer of CYP1A1 is
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, TCDD induces a broad spectrum of biochemical and toxic effects, such as teratogenesis, immunosuppression and tumor promotion. Most, if not all, of the effects caused by TCDD and other polycyclic aromatic hydrocarbons (PAHs) are known to be mediated by AhR which has a high binding affinity to TCDD. ==Protein-protein interactions==