Effects of thiamin antagonists on drug hydroxylation and properties of cytochrome P-450 in the rat

The administration of small amounts of thiamin (0.3 $\text{μg}\text{day}$ or more, i.p., for 21 days) depressed musomal cytochrome P-450 content and the V_max of aniline hydroxylase when compared to values obtained from rats fed a thiamin-deficient diet (approximately 0.1 μg of thiamine/day in basal diet). The concurrent administration of neopyrithiamin (50 $\text{μg}\text{day}$, i.p.) eliminated the depressant effect of 10.0 μig of thiamin/ day, but was without significant effect in rats receiving more than 100 μg of thiamin/ day. In contrast, 100 μg of oxythiamin/day had no thiamin-opposing effect on cytochrome P-450 content and only partially counteracted the effects of 1 μg of thiamin/day on aniline hydroxylase activity. These treatments were without significant effect on the K_m for this reaction. Using ethyl isocyanide as the ligand, there appears to be a qualitative change induced in the cytochrome P-450 from thiamin-deficient rats. The absorption peak height ratios indicate that cytochrome P₁-450 is increased in a manner analogous to that produced by the administration of 3-methylcholanthrene. This was supported by the fact that aniline binding, as evidenced by increased ΔA_max, is enchanced in musomes from thiamin-deficient animals, whereas the hexobarbital spectral shift was unaltered.