CYP17 polymorphism and tamoxifen-induced hepatic steatosis.

[aromatase deficiency]

Hepatic steatosis is a frequent complication , which sometimes develops nonalcoholic steatohepatitis (NASH ), in breast cancer patients treated with tamoxifen , a potent antagonist of estrogen . Recently we reported the impairment of fatty acid beta -oxidation and the enhancing fatty infiltration to hepatocytes in aromatase deficiency (ArKO ) mice as the estrogen deficiency models . This experimental observation let us speculate strong link between estrogen and hepatic steatosis . In this study , we investigated whether a polymorphism in the cytochrome P 450 c 17 alpha gene (CYP 17 ), which is associated with circulating estrogen levels , influences the development of tamoxifen-induced hepatic steatosis . This consecutive study included 180 breast cancer patients undergoing tamoxifen treatment . Genomic DNA extracted from the peripheral blood of each patient was analyzed by restriction fragment length polymorphism (defined as the A 1 and A 2 alleles ). The extent of hepatic steatosis was assessed by computed tomography (CT ) as the liver /spleen (L /S ) ratio . While receiving adjuvant tamoxifen , 57 of 180 patients developed hepatic steatosis (L /S ratio <0 .9 ) without obvious changes in body mass index (BMI ). We observed a significant association between the A 2 /A 2 genotype and the development of hepatic steatosis compared with the A 1 /A 1 genotype [odds ratio (OR ), 3 .60 ; 95 % confidence interval (C .I .)=1 .42 -9 .10 ]. The A 1 /A 2 genotype was at an intermediately increased risk of hepatic steatosis (OR , 2 .24 ; 95 % C .I .=0 .99 -5 .08 ). The presence of the A 2 allele possibly increased the progression of hepatic steatosis with a gene dosage effect (P =0 .06 ). Our results suggest that functional polymorphism in CYP 17 may be involved in determining susceptibility of tamoxifen-induced hepatic steatosis .

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aromatase deficiency

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