Low Activity of Cytochrome P450 1A2 (CYP1A2) Enzyme May Protect From Iron Accumulation in Children and Adults with Transfusion Depended β-Thalassemia Major
Authors: Revel-Vilk Shoshana , Nitzan Itamar , Goldfarb Ada , Hemed Nilla , Shteyer Eyal 
Published: October 2019

Abstract
Abstract 2153
In human, normal iron homeostasis fails to prevent the harmful accumulation of iron in patients who require regular blood transfusions. Some patients will progress to liver fibrosis and cirrhosis, but others, with the same degree of iron overload, would not express any liver damage. Cytochrome P450 1A2 (CYP1A2), a cytochrome enzyme with pivotal role in hepatic drug metabolism, was shown in a CYP1A2−/− mice to be essential for hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to iron load in children and adults with transfusion-depended β-thalassemia major (TM) using the 13C-methacetin breath test.

Methods:
13 C-methacetin continuous online breath test (MBT, BreathID® Exalenz Bioscience) was performed in children and adults with transfusion-depended TM. MBT parameters including PDR peak (percent dose recovered per hour), cumulative percentage of 13C recovery at 20 minutes (CPDR20) after ingestion of methacetin and time to peak PDR (TTP) were correlated with various clinical, blood and MRI measures. The t-test was used to assess difference of normally distributed continuous data, Mann-Whitney test was used to assess difference of non-normally distributed continuous data and the Fisher's exact test was used to assess differences of categorical data. The study was approved by the Institutional Review Board.

Results:
Thirty patients [Jewish Kurdistan origin (n=14), Arab origin (n=16)] were enrolled to the study. The median (range) age of participants was 30 (1–60) years. All patients were treated with regular blood transfusion and all but one patient, were treated with iron chelation therapy [Deferoxamine (n =4), Deferiprone (n=2), Deferasirox (n=15), Combinations (n=7)]. Time from starting regular transfusion ranged from 0.8–56 years. Mean red blood cell (RBC) transfused was 100 cc/kg/year. Plasma ferritin level < 1000 mcg/l was found in 14 patients, and was not associated with age, origin, time of initiation of regular blood transfusion and amount of RBC transfusion. The PDR peak and CPDR20 were significantly lower in patients with ferritin levels < 1000 mcg/l compared to those with ferritin levels > 1000 mcg/l (PDR peak, mean±SD: 24±8 vs. 31± 10, p=0.013; CPDR20: 3.9± 2 vs. 5.5± 2.2, p=0.045, t-test). During the study period, 21 patients had T2* MRI scans. Liver MRI was normal (T2* MRI > 6.3 milliseconds) in 8 patients, and was not associated with age, origin, time of initiation of regular blood transfusion and amount of RBC transfusion. As expected, plasma ferritin levels were significantly lower in patients with normal liver MRI (Ferritin, median (range): 376 (110–1506) vs.1349 (205–8223), p=0.008, Mann-Whitney test). Decreased activity of CYP1A2 (PDR peak < 20%/hour) was associated with normal liver MRI (Table 1). All patients with decreased activity of CYP1A2 and normal liver MRI were from Jewish Kurdistan origin.

Conclusions:
Our study is the first to show an association between low activity of CYP1A2 and low liver iron accumulation in transfusion depended TM patients. Similar to the murine model, this finding may suggest that primary low CYP1A2 activity protects from iron accumulation. The fact that CPY1A2 activity in most patients with liver iron accumulation is normal implies that decreasing dosage of various drugs is probably not warranted in patients with hepatic iron overload. Further larger studies and genetic testing are needed to confirm our observations.

Disclosures:
No relevant conflicts of interest to declare.