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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1346
Copyright © 2000 by The Endocrine Society

Letters to the Editor

Role of Cytochrome b5 in the 17,20-Lyase Activity of P450c17

Walter L. Miller and Richard J. Auchus

Department of Pediatrics University of California–San Francisco San Francisco, California 94143-0978

In the September 1999 issue of this journal, Mapes et al. (1) reported the important observation that cytochrome b5 is preferentially expressed in the monkey zona reticularis, consistent with the biochemical observation that the presence of b5 promotes the 17,20-lyase activity of human P450c17. This b5 mediated effect was first reported in 1982 (2), confirmed in 1992 and 1995 (3, 4), and the mechanism by which b5 exerts its activity as an allosteric factor, rather than as an electron donor, was established with human systems in 1998 (5). Mapes et al. (1) state that the demonstration that P450c17 has both 17{alpha}-hydroxylase and 17,20-lyase activities has fueled debate about the mechanism by which 17,20-lyase activity is regulated, in view of the existence of patients with isolated 17,20-lyase deficiency. There is little remaining debate as the genetic and biochemical basis of isolated 17,20-lyase deficiency is now known. The molecular basis of 17,20-lyase deficiency was determined in two patients by Geller et al. (6) and in a third patient by Biason-Lauber et al. (7), identifying missense mutations in the redox-partner binding-site in all three cases. The mechanism by which these mutations cause loss of lyase but not hydroxylase activity has been shown in the two index cases to be due to disrupted interactions with both P450 oxidoreductase (6) and with cytochrome b5 (8). The mechanism by which mutations in the region of P450c17 that participates in redox partners interactions has been established genetically, biochemically, and structurally (9). Definitive understanding of the role of b5 will require the study of b5-deficient patients that will represent a gene knockout of nature; a mouse knockout would provide less information because rodents do not express P450c17 in their adrenals (10). The principal known physiologic role of cytochrome b5 is in reducing methemoglobin, but most patients with hereditary methemoglobinemia have defects in cytochrome b5 reductase rather than in b5 itself (11). Only one patient with cytochrome b5 deficiency has been reported (12) and studied at a molecular genetic level (13). That patient was a male pseudohermaphrodite who had female genitalia at birth, but, unfortunately, data concerning adrenal and gonadal steroidogenesis have not been reported for this patient. In a converse experiment of nature, Sakai et al. (14) reported that adrenal adenomas that overproduce 19-carbon steroids and, hence, have abundant 17,20-lyase activity contain very large amounts of cytochrome b5. Thus, the report of Mapes et al. (1) and a related report by Yanase et al. (15) concerning the human adrenal provide further anatomical evidence for the established central role of cytochrome b5 in regulating the 17,20-lyase activity of human P450c17.

Footnotes

Address correspondence to: Walter L. Miller, Department of Pediatrics, University of California–San Francisco, Building MR-4, Room 209, San Francisco, California 94143-0978.

Received October 12, 1999.

References

  1. Mapes S, Corbin C, Tarantal A, Conley A. 1999 The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17{alpha}-hydroxylase/17,20-lyase cytochrome P450 (P450c17) and NADPH-cytochrome P450 reductase (reductase) but not 3ß-hydroxysteroid dehydrogenase/{Delta}5-4 isomerase (3ß-HSD). J Clin Endocrinol Metab. 84:3382–3385.[Abstract/Free Full Text]
  2. Onoda M, Hall PF. 1982 Cytochrome b5 stimulates purified testicular microsomal cytochrome P450 (C21 side-chain cleavage). Biochem Biophys Res Commun. 108:454–460.[Medline]
  3. Kominami S, Ogawa N, Morimune R, Huang DY, Takemori S. 1992 The role of cytochrome b5 in adrenal microsomal steroidogenesis. J Steroid Biochem Mol Biol. 42:57–64.[CrossRef][Medline]
  4. Lee-Robichaud P, Wright JN, Akhtar ME, Akhtar M. 1995 Modulation of the activity of human 17{alpha}-hydroxylase-17,20-lyase (CYP17) by cytochrome b5: endocrinological and mechanistic implications. Biochem J. 308:901–908.
  5. Auchus RJ, Lee TC, Miller WL. 1998 Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer. J Biol Chem. 273:3158–3165.[Abstract/Free Full Text]
  6. Geller DH, Auchus RJ, Mendonça BB, Miller WL. 1997 The genetic and functional basis of isolated 17,20 lyase deficiency. Nat Genet. 17:201–205.[CrossRef][Medline]
  7. Biason-Lauber A, Leiberman E, Zachmann M. 1997 A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20 lyase deficiency. J Clin Endocrinol Metab. 82:3807–3812.[Abstract/Free Full Text]
  8. Geller DH, Auchus RJ, Miller WL. 1999 P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol. 13:167–175.[Abstract/Free Full Text]
  9. Auchus RJ, Miller WL. 1999 Molecular modeling of human P450c17 (17{alpha}-hydroxylase/17,20-lyase): Insights into reaction mechanisms and effects of mutations. Mol Endocrinol. 13:1169–1182.[Abstract/Free Full Text]
  10. Voutilainen R, Tapanainen J, Chung B, Matteson KJ, Miller WL. 1986 Hormonal regulation of P450scc (20,22-desmolase) and P450c17 (17{alpha}-hydroxylase/17,20-lyase) in cultured human granulosa cells. J Clin Endocrinol Metab. 63:202–207.[Abstract]
  11. Jaffe E, Hulquist D. 1989 Cytochrome b5 reductase deficiency and enzymoperic hereditary methemoglobinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw Hill.
  12. Hegesh E, Hegesh J, Kaftory A. 1986 Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med. 318:757–761.
  13. Giordano SJ, Kaftory A, Steggles AW. 1994 A splicing mutation in the cytochrome b5 gene from a patient with congenital methemoglobinemia and pseudohermaphrodism. Hum Genet. 93:568–570.[Medline]
  14. Sakai Y, Yanase T, Takayanagi R, et al. 1993 High expression of cytochrome b5 in adrenocortical adenomas from patients with Cushing’s syndrome associated with high secretion of adrenal androgens. J Clin Endocrinol Metab. 76:1286–1290.[Abstract]
  15. Yanase T, Sasano H, Yubisui T, Sakai Y, Takayanagi R, Nawata H. 1998 Immunohistochemical study of cytochrome b5 in human adrenal gland and in adrenocortical adenomas from patients with Cushing’s syndrome. Endocr J. 45:89–95.[Medline]



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