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Catalysis of the Covalent Binding of 3-Hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole to DNA by a L-Proline- and Adenosine Triphosphate-dependent Enzyme in Rat Hepatic Cytosol¹

Department of Pharmacology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan

An enzymatic mechanism involved in the activation of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-hydroxy-Trp-P-2), a mutagenic intermediate of a tryptophan pyrolysate, was studied in vitro. In hepatic cytosol supplemented with adenosine triphosphate and L-proline, N-hydroxy-Trp-P-2 was converted to a form which reacts readily with DNA. The enzyme responsible for the activation was partially purified and identified as prolyl transfer RNA synthetase as judged by their cofactor requirements, inhibition by pyrophosphate or adenosine monophosphate, and copurification of their activities.

The prolyl transfer RNA-dependent covalent binding of N-hydroxy-Trp-P-2 to DNA of hepatic cytosol was highest in rats, followed by mice, hamsters, rabbits, and guinea pigs in that order. The capacity for the binding of N-hydroxy-Trp-P-2 was largely consistent with their prolyl transfer RNA synthetase activity.

With regard to the ultimate form of N-hydroxy-Trp-P-2 for the covalent binding, a possible formation of N,O-prolyl-3-amino-1-methyl-5H-pyrido[4,3-b]indole was proposed.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan, the Ministry of Education, Science and Culture of Japan, and an additional grant from the Princess Takamatsu Cancer Research Fund.

² To whom requests for reprints should be addressed.

Received 8/ 6/84. Revised 12/26/84. Accepted 2/28/85.