In contrast to deferoxamine (DFO), the orally bioactive chelator deferiprone (DMHP) has a structure predicted to inhibit prolyl 4-hydroxylase[EC 1.14,11.2], the key metalloenzyme in the biosynthesis of collagens and collectins. DMHP, but not DFO, inhibited the enzyme in human collagen-producing cells with IC50s at concentrations achieved in patients. In a pilot study, we therefore followed the serum levels of procollagen-derived antigens in two thalassemics receiving an experimental course of both chelators.

Patients A and B, each with a clinical and molecular diagnosis ofβ-thalassemia major, are 25 year old males of Mediterranean extraction, on a hypertransfusion protocol, and had been chelated with DFO since age 7. Ferritin levels over the past year averaged 1230 and 870 ng/ml, respectively. Both patients had no cardiac disease but were hepatitis C positive without overt hepatitis. The experimental protocol compared iron chelation efficacy of DMHP versus DFO [days 5-10, DMHP at 75 mg/kg/d p.o. TID; days 15-20, DFO at 60 mg/kg/d s.c.; days 1-4, 11-14, and 21-24, wash-out periods].

Serum levels of the C-terminal propeptide of procollagen type I (PICP) and the N-terminal propeptide of procollagen type III were monitored. Mean PICP level at baseline in Patients A and B were 147 and 141 ng/ml, respectively(normal males: 38-202 ng/ml). In Patient A, PICP levels decreased by 24% after 6 days on DMHP; in Patient B, they decreased by 34%, with the nadir 4 days after deferiprone was discontinued. Mean PIIINP baseline levels were 7.9 and 5.1 ng/ml, respectively, and thus were elevated compared to normal males(1.7-4.2 ng/ml). PIIINP levels decreased by 22% and 13%, respectively, 4 days after deferiprone withdrawal. DFO administration did not reduce the serum concentration of either PICP or PIIINP. These in vivo results indicate that metal chelation per se cannot account for the observed reduction in biosynthesis of the major fibrillar procollagens as reflected by the serum levels of their propeptides.

Our findings suggest that patients on long-term DMHP medication should be carefully monitored for clinical correlates of prolyl 4-hydroxylase inhibition with resultant suppression of collagen and/or collectin biosynthesis, such as connective tissue alterations of insidious onset or immune system disturbances caused by inadequate C1q function. On the other hand, following further toxicity studies in patients not iron-overloaded, short-term high-dose administration of DMHP may allow therapeutic utilization of its antifibrotic effect in specific clinical settings, and may be particularly useful for control of iatrogenically triggered fibrotic complications such as coronary restenosis post angioplasty or chemotherapy-induced lung fibrosis.Supported in part by FDA FD-R-001050-01-03