CYP4F12

Gene family

The CYP4F12 gene encodes a member of the cytochrome P450 superfamily of enzymes. It is located within a cluster of P450 genes on chromosome 19. Cytochrome P450 proteins are monooxygenases that catalyze a wide array of reactions involved in drug metabolism and in the synthesis of cholesterol, steroids, and other lipids.

Expression and localization

CYP4F12 is thought to localize to the endoplasmic reticulum. It is expressed in the liver and throughout the gastrointestinal tract. The enzyme is known to metabolize the antihistamines ebastine and terfenadine, suggesting it may play a role in the metabolism of these and other drugs.

Substrate specificity

When expressed in yeast, CYP4F12 oxidizes arachidonic acid by hydroxylating carbon 18 or 19 to form 18-HETE or 19-HETE, respectively, though the physiological significance of this activity remains unclear. It also metabolizes prostaglandin H2 (PGH2) and PGH1 to their 19-hydroxyl analogs, potentially reducing their biological activity.

In addition to monooxygenase activity, CYP4F12 also functions as an epoxygenase. It metabolizes docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two omega-3 fatty acids, to produce epoxide derivatives: DHA → 19R,20S- and 19S,20R-epoxydocosapentaenoic acids (19,20-EDP) EPA → 17R,18S- and 17S,18R-epoxyeicosatetraenoic acids (17,18-EEQ).

Function

19-HETE, one of CYP4F12’s products, inhibits the activity of 20-HETE, a pro-inflammatory and vasoconstrictive signaling molecule. However, the in vivo importance of this inhibition has yet to be confirmed (see 20-Hydroxyeicosatetraenoic acid). EDPs (see Epoxydocosapentaenoic acid) and EEQs (see epoxyeicosatetraenoic acid) exhibit a wide range of biological activities in animal models and in vitro systems:

• Lower blood pressure and pain perception
• Suppress inflammation
• Inhibit angiogenesis, endothelial cell migration and proliferation]
• Inhibit growth and metastasis of breast and prostate cancer cell lines]

These findings suggest that EDPs and EEQs may contribute to the beneficial effects of dietary omega-3 fatty acids such as DHA and EPA in humans. These metabolites are short-lived and are rapidly inactivated by epoxide hydrolases, particularly soluble epoxide hydrolase, limiting their action to local environments.

Comparison with CYP4F8

CYP4F12 shares similar enzymatic activity with CYP4F8, particularly in fatty acid metabolism and epoxide formation. However, neither enzyme is considered a major contributor to these processes in humans, although they may play important roles in tissues where they are highly expressed.

References

References

1. (Feb 2001). "cDna cloning and expression of CYP4F12, a novel human cytochrome P450". Biochemical and Biophysical Research Communications.
2. "Entrez Gene: CYP4F12 cytochrome P450, family 4, subfamily F, polypeptide 12".
3. (September 2005). "Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8". Archives of Biochemistry and Biophysics.
4. (January 2015). "Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer".
5. (November 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators.
6. (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews.
7. (January 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research.
8. (October 2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators.
9. (March 2014). "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research.
10. (December 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes.