Quantitation of multiple pathways for the metabolism of nephrotoxic cysteine conjugates using selective inhibitors of L-alpha-hydroxy acid oxidase (L-amino acid oxidase) and cysteine conjugate beta-lyase

Journal Article · Mon May 01 00:00:00 EDT 1989 · Drug Metabolism and Disposition; (USA)

OSTI ID:5477659

Stevens, J L; Hatzinger, P B; Hayden, P J ^[1]

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1. W. Alton Jones Cell Science Center, Inc., Lake Placid, NY (USA)

In this study, we have established the selectivity of inhibitors for rat kidney cysteine conjugate beta-lyase and L-alpha-hydroxy acid oxidase (L-amino acid oxidase) and have used these inhibitors to explore the relative roles of these two enzymes in the metabolism of nephrotoxic cysteine conjugates by rat kidney homogenate. In addition, we have investigated the relationship between structure and the metabolism of toxic cysteine conjugates by purified rat kidney L-alpha-hydroxy acid oxidase. With purified enzyme, S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBDC) was about four times more active than S(1,2-dichlorovinyl)-L-cysteine (DCVC). Three alkyl conjugates were less active than DCVC. Purified L-alpha-hydroxy acid oxidase was not inhibited by the beta-lyase inhibitor aminooxyacetic acid but was inactivated by 2-hydroxy-3-butynoate. PCBDC metabolism in rat kidney homogenate was inhibited 74% by aminooxyacetic acid and 42% by 2-hydroxy-3-butynoate, whereas DCVC metabolism was inhibited 77% by aminooxyacetic acid and 28% by 2-hydroxy-3-butynoate. However, only aminooxyacetic acid inhibited the binding of {sup 35}S label from ({sup 35}S)DCVC. Based on these results we have reached three conclusions. First, L-alpha-hydroxy acid oxidase plays a significant role in the metabolism of some cysteine conjugates. Second, metabolism of DCVC by L-alpha-hydroxy acid oxidase does not contribute directly to covalent binding. Third, as much as 65% of DCVC may be metabolized to its corresponding alpha-keto acid. The results are discussed with regard to the nephrotoxicity of cysteine conjugates.

• OSTI ID: 5477659
• Journal Information: Drug Metabolism and Disposition; (USA), Vol. 17:3; ISSN 0090-9556
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CYSTEINE
METABOLISM
ENZYME INHIBITORS
BIOCHEMICAL REACTION KINETICS
LYASES
BIOLOGICAL FUNCTIONS
OXIDOREDUCTASES
ACETIC ACID
BIOLOGICAL PATHWAYS
IN VITRO
KIDNEYS
RATS
STRUCTURE-ACTIVITY RELATIONSHIPS
SULFUR 35
TOXICITY
TRACER TECHNIQUES
UROGENITAL SYSTEM DISEASES
AMINO ACIDS
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
CARBOXYLIC ACIDS
DAYS LIVING RADIOISOTOPES
DISEASES
ENZYMES
EVEN-ODD NUCLEI
FUNCTIONS
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIGHT NUCLEI
MAMMALS
MONOCARBOXYLIC ACIDS
NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
RADIOISOTOPES
REACTION KINETICS
RODENTS
SULFUR ISOTOPES
THIOLS
VERTEBRATES
550501* - Metabolism- Tracer Techniques