Effects of repeated administration of rifampicin and isoniazid on vitamin D metabolism in mice

Vitamin D deficiency is prevalent in tuberculosis (TB) patients and the anti-TB drugs, especially rifampicin (RIF) and isoniazid (INH), are associated with altered endocrine actions of vitamin D. Although it is well-known that these two drugs can affect a variety of cytochrome P450 (CYP450) activity, their influence on the CYP450 enzymes involved in vitamin D metabolism remains largely unknown. To fill this critical gap, serum vitamin D status and the expression of hepatic CYP2R1 and CYP27A1 and renal CYP27B1 and CYP24A1 were assessed in mice following 3-week exposure to 100 mg/kg/day RIF or (and) 50 mg/kg/day INH. Unexpectedly, we found either RIF or co-treatment the two drugs increased the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), without affecting 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) status. In parallel, enhanced hepatic expressions of 25-hydroxylase enzymes, CYP2R1 and (or) CYP27A1, were found in RIF and RIF + INH groups. However, co-administration of RIF and INH inhibited the expression of CYP27B1, while inducing CYP24A1 expression. Collectively, our data firstly showed that RIF and co-treatment of RIF and INH can both enhance 25-hydroxylation and 24-hydroxylation of vitamin D, providing novel evidence for the involvement of anti-TB drugs in the metabolism of vitamin D.