Biotin Deficiency in Rats: Disturbances of Leucine Metabolism are Detectable Early

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Abstract
3-Methylcrotonyl-CoA originates from catabolism of leucine and is normally metabolized to acetyl-CoA. However, in biotin deficiency, reduced hepatic activity of the biotin-dependent enzyme methylcrotonyl-CoA carboxylase causes the enzyme's substrate 3-methylcrotonyl-CoA to be shunted via an alternate pathway to 3-hydroxyisovaleric acid (3-HIA), which is excreted at increased rates in the urine. In a previous study, unequivocal separation in 3-HIA excretion rates between biotin-deficient and control animals was not apparent until d 35 of feeding a diet that induced biotin deficiency. The present study tested the hypothesis that abnormal 3-HIA excretion could be detected earlier in the course of biotin deficiency if 3-HIA were more accurately measured using a method that incorporated an improved extraction regimen, deuterated 3-HIA as internal standard, and unlabeled 3-HIA as external standard. Biotin deficiency was induced in rats by feeding a diet containing avidin; control rats received the same diet and biotin injections. With the more accurate method, unequivocal detection of deficiency was possible in all deficient rats by d 16. This study provides evidence that, in rats, reduction of analytical error allows earlier detection of biotin deficiency and that disturbances of leucine metabolism occur earlier than previously appreciated.