Effect of two mutations of human CYP1B1, G61E and R469W, on stability and endogenous steroid substrate metabolism.

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Jansson I, Stoilov I, Sarfarazi M, Schenkman JB

Effect of two mutations of human CYP1B1, G61E and R469W, on stability and endogenous steroid substrate metabolism.

Pharmacogenetics. 2001 Dec;11(9):793-801.

PubMed ID

11740343 [ View in PubMed

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Abstract

CYP1B1 is linked to normal eye development by the disease phenotype, primary congenital glaucoma (PCG). CYP1B1 mRNA was expressed in a number of human fetal tissue cDNA libraries, supporting the suggestion of its involvement in tissue development. Highest expression levels were found in thymus and kidney, followed by spleen. A considerably lower level was observed in lung, cardiac and skeletal muscle. No expression was detected in liver or brain. CYP1B1 is able to metabolize steroid hormones. Testosterone was a poor substrate and activity with progesterone was 6-fold higher, but estradiol was the preferred substrate, exhibiting a greater metabolite profile with CYP1B1 than with CYP1A2. Major metabolites were A-ring hydroxylations (75-80%). Others were 15alpha-, 6alpha-, 16alpha- and 6beta-hydroxy metabolites. Two CYP1B1 mutations found in families with the PCG phenotype in which incomplete penetrance is seen were expressed in Escherichia coli. G61E, a hinge region mutation, and R469W, a heme region mutation, were shown to code for holoenzymes. G61E had greatly diminished stability, while the R469W holoenzyme, if anything, was stabilized. Both mutants showed compromised catalytic activity. The extents of isomeric site activity diminution were not proportional, resulting in alterations in the metabolite profiles. The results suggest that if a metabolite of CYP1B1 or elimination of a metabolite by CYP1B1 is necessary for normal embryonic or fetal tissue development, the appearance of these two mutations could result in developmental abnormalities. The altered activities of the mutants and ability of CYP1B1 to respond to external challenge may be the basis for the observed incomplete penetrance.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Progesterone	Cytochrome P450 1B1	Protein	Humans	Unknown	Substrate	Details