Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus

Abstract

OBJECTIVE: Ovarian toxicity is a major concern with cyclophosphamide (CYC) therapy. CYC is a prodrug that is activated by cytochrome P450 (CYP) enzymes to its active metabolites that are responsible for ovarian toxicity. The amount of active metabolites produced depends on polymorphism in CYP 450 genes. We studied the association of CYP2C19 and CYP2B6 genetic polymorphism with ovarian toxicity in patients with systemic lupus erythematosus (SLE) treated with CYC. METHODS: Thirty-five patients with SLE who had exposure to CYC were genotyped for variant alleles of CYP2B6 and CYP2C19. Ovarian toxicity included ovarian insufficiency, defined as lack of menses for 4 months, and ovarian failure (premature menopause) as amenorrhea lasting > 12 months before the age of 45 years. RESULTS: The mean age at start of CYC was 24.5 + 8.5 years and the cumulative dose of CYC received was 9.3 +/- 2.8 g. At the time of study the median followup after CYC treatment was 3 (1-6) years. A total of 17 patients developed ovarian toxicity, of whom 11 patients had ovarian insufficiency and 6 had premature menopause. The frequencies of variant alleles CYP2B6*5 and CYP2C19*2 were 8.5% and 21%, respectively. Patients who were homozygous or heterozygous for variant allele CYP2C19*2 had a significantly lower risk of developing ovarian toxicity when compared to patients with wild-type allele CYP2C19*1 (3/13 vs 14/22; OR 0.136, 95% CI 0.028-0.653; p < 0.01). No association was seen with CYP2B6 polymorphism. CONCLUSION: Presence of the variant allele CYP2C19*2 is associated with lower risk of ovarian toxicity in Indian patients treated with CYC.