Editing CYP3A4 (section)

== Induction ==
CYP3A4 is [[Enzyme induction and inhibition|induced]] by a wide variety of [[Ligand (biochemistry)|ligand]]s. These ligands bind to the [[pregnane X receptor]] (PXR). The activated PXR complex forms a heterodimer with the [[retinoid X receptor]] (RXR), which binds to the [[XREM]] region of the ''CYP3A4'' gene. XREM is a regulatory region of the ''CYP3A4'' gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates [[Transcription (genetics)|transcription]] of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of [[aflatoxins|aflatoxin]] B1, M1, and G1. Indeed, due to the enzyme's large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.<ref name="pmid21641981">{{cite journal | vauthors = Ratajewski M, Walczak-Drzewiecka A, Sałkowska A, Dastych J | title = Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor | journal = Toxicology Letters | volume = 205 | issue = 2 | pages = 146–53 | date = August 2011 | pmid = 21641981 | doi = 10.1016/j.toxlet.2011.05.1034 }}</ref>

Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased [[clearance (pharmacology)|drug clearance]] by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that the median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 [[messenger RNA|mRNA]] transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women.<ref name="pmid14512885">{{cite journal | vauthors = Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM | title = Sex is a major determinant of CYP3A4 expression in human liver | journal = Hepatology | volume = 38 | issue = 4 | pages = 978–88 | date = October 2003 | pmid = 14512885 | doi = 10.1053/jhep.2003.50393 | doi-access =  }}</ref>

CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by [[rifampicin]] and human PXR is not activated by pregnenolone 16α-carbonitrile<ref name="Gonzalez">{{cite journal | vauthors = Gonzalez FJ | title = CYP3A4 and pregnane X receptor humanized mice | journal = Journal of Biochemical and Molecular Toxicology | volume = 21 | issue = 4 | pages = 158–62 | year = 2007 | pmid = 17936928 | doi = 10.1002/jbt.20173 | s2cid = 21501739 | url = https://zenodo.org/record/1229206 | access-date = 6 September 2019 | archive-date = 29 July 2020 | archive-url = https://web.archive.org/web/20200729031129/https://zenodo.org/record/1229206 | url-status = live }}</ref> In order to facilitate study of CYP3A4 functional pathways ''in vivo,'' mouse strains have been developed using [[transgene]]s in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in the liver.<ref name="Gonzalez" /> This effect has been attributed to CYP3A4 regulation by the [[growth hormone]] signal transduction pathway.<ref name="Gonzalez" /> In addition to providing an ''in vivo'' model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.<ref name="Gonzalez" />

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.<ref name="Crago">{{cite journal | vauthors = Crago J, Klaper RD | title = Influence of gender, feeding regimen, and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows ({{lang|la|Pimephales promelas}}) | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 154 | issue = 3 | pages = 208–12 | date = September 2011 | pmid = 21664292 | doi = 10.1016/j.cbpc.2011.05.016 }}</ref> Due to the enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation.<ref name="Crago" /> By studying animal models and keeping in mind the innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways.