Clues

[Guest guest]

Dear All;

In the last couple of years we've seen that the receptor pregnane X

receptor [PXR] (also known as steroid and xenobiotic receptor [sXR])

seems to be playing an important role in IBD and possibly PSC. PXR

regulates the expression of a number of bile transport proteins and

enzymes of bile metabolism and drug/xenobiotic metabolism in the

liver.

The first important clue is that in ulcerative colitis the

expression of PXR is often down-regulated, resulting in impaired

expression of bile transport proteins such as ABCB1 (MDR1):

Langmann T., et al. 2004. Loss of detoxification in inflammatory

bowel disease: dysregulation of pregnane X receptor target genes.

Gastroenterology. 127:26–40.

Impaired expression of MDR1 due to genetic polymorphisms in the MDR1

gene has been associated with ulcerative colitis:

Ho GT et al.(2006) ABCB1/MDR1 gene determines susceptibility and

phenotype in ulcerative colitis: discrimination of critical variants

using a gene-wide haplotype tagging approach. Hum. Mol. Genet.

15:797-805.

A second important clue is that polymorphisms in the PXR gene are

also associated with inflammatory bowel disease:

Dring M.M., et al. 2006. The pregnane X receptor locus is associated

with susceptibility to inflammatory bowel disease. Gastroenterology.

130:341–348.

I can recommend this Medscape article " Pregnane X Receptor

Polymorphisms Linked to Inflammatory Bowel Disease " for an

explanation of the significance of this:

http://www.medscape.com/viewarticle/525655

A third clue is that polymorphisms in the PXR/SXR gene seem to

determine disease course/survival in PSC:

Karlsen T.H., et al. (2006) Polymorphisms in the steroid and

xenobiotic receptor gene influence survival in primary sclerosing

cholangitis. Gastroenterology 131: 781-787.

A fourth important piece of the puzzle is that PXR/SXR affects the

inflammation pathway at the level of nuclear factor-kappaB (NF-kB),

and vice versa. In other words, active inflammation can suppress

PXR/SXR; conversely activation of PXR/SXR can inhibit inflammation.

So there is direct cross-talk between the inflammation and

xenobiotic metabolism pathways:

Zhou C. et al. (2006) Mutual repression between steroid and

xenobiotic receptor and NF-kB signaling pathways links xenobiotic

metabolism and inflammation. J. Clin. Invest. 116:2280-2289.

http://www.jci.org/cgi/content/full/116/8/2280

Rifampin (rifampicin) is an activator of PXR/SXR, and this may in

part explain the effects of rifampin on the suppression of

itching/pruritus in cholestatic liver diseases. The latter paper

begins to explain some of the immunosuppressive effects of rifampin.

There is some evidence that ursodeoxycholic acid might also be

influencing this receptor.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)