Figure 8-19 Crucial steps in the β-lyase pathway: First, conjugation of compound A with glutathione in the liver is mediated by glutathione S-transferase; this conjugate is then transported to the kidney. Second, the glutathione S-conjugate is converted to a cysteine S-conjugate, a process mediated by γ-glutamyl transpeptidase. Third, the cysteine S-conjugate of compound A is then converted to a reactive thiol, mediated by renal cysteine conjugate β-lyase; DL-buthionine-(S,R)-sulfoximine (BSO) depletes endogenous stores of glutathione in the body, acivicin (AT-125) inhibits the activity of γ-glutamyl transpeptidase, and aminooxyacetic acid (AOAA) inhibits the activity of β-lyase. Compound A, its conjugates, and the reactive thiol have all been postulated to cause the renal necrosis that can occur in rats after the administration of compound A and the glucosuria and enzymuria that can result in rats and humans from compound A administration.