Human Delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism.

Conclusive in vivo evidence regarding the enzyme responsible for steroid hormone 5beta-reduction has not been obtained, although studies have suggested it may be the same enzyme as that utilized for cholic acid and chenodeoxycholic bile-acid synthesis. We have recorded the steroid metabolome of a patient with a defect in the "bile-acid" 5beta-reductase (AKR1D1) and from this confirm that this enzyme is additionally responsible for steroid hormone metabolism. The 13-year old patient has been investigated since infancy because of a cholestasis phenotype caused by bile-acid insufficiency. Several years ago it was shown that she had a 662C>T missense mutation in AKR1D1 causing a Pro198Leu substitution. It was found that the patient had an almost total absence of 5beta-reduced metabolites of corticosteroids and severely reduced production of 5beta-reduced metabolites of other steroids. The patient is healthy in spite of her earlier hepatic failure and is on no treatment. All her vital signs were normal, as were results of many biochemical analyses. She had normal pubertal changes and experiences regular menstrual cycles. There was no evidence for any clinical condition that could be attributed to attenuated ability to metabolize steroids in normal fashion. Both parents were heterozygous for the mutation but the steroid excretion was entirely normal, although an older female sibling showed definitive evidence for attenuated 5beta-reduction of cortisol. A younger brother had a normal steroid metabolome. The sibling genotypes were not available.