Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs

Abstract

Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

“…Manifestations of (sub)clinical folate deficiency requiring folate supplementation had been reported previously during SSZ single-drug therapy in patients with RA (17)(18)(19)(20)(21)(22). Thus far, the mechanisms proposed to underlie these effects were inhibitory effects of SSZ on intestinal folate absorption (25)(26)(27) and several enzymes in intracellular folate metabolism (23,24).…”

“…Thus, original reports of impaired intestinal folate absorption following SSZ treatment (25)(26)(27) can be attributed to direct inhibition of intestinal RFC by SSZ. Complementary inhibitory effects of SSZ on enzymes in folate metabolism (23,24) may then further aggravate the folate-deficient status.…”

“…Furthermore, one notable adverse effect observed was a persistent increase in plasma homocysteine levels in patients with RA who were receiving the combination of MTX and SSZ, compared with those receiving single-drug therapy (15,16). Elevated plasma homocysteine levels are associated with cellular folate depletion (17)(18)(19)(20)(21)(22), which has been ascribed to the inhibitory effects of SSZ on several intracellular enzymes involved in folate metabolism (23,24) and/or inhibition of intestinal folate uptake (25)(26)(27).…”

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

“…Previous studies have shown that Folate Receptor 1 (FOLR1) [33][34][35][36] is up-regulated due to folate depletion in vitro, while it is the reduced folate carrier (RFC) that is upregulated in the rat intestine [37,38], with the FOLR1 remaining undetectable [38]. Increased FOLR1 in vitro and the increased RFC in vivo reflect the abundance of available forms in the particular model and the affinity of each protein for them.…”

Pregnancy and inflammatory bowel diseases: Current perspectives, risks and patient management

“…Sulfasalazine (SSZ), the first aminosalicylate used in treating IBD, is an FDA category "B" drug. Since SSZ crosses the placenta, there are several concerns in pregnancy [67] . SSZ is known to inhibit folate synthesis [68] and impairs folate absorption potentially leading to fetal neural tube defects.…”