JAN 2 198

CHEMICAL INDUSTRY INSTITUTE OF TOXICOLOGY

PRESIDENT, LEON GOLBERG, M.B., D.Sc., D.PHIL., FRIC, FRCParH.
VICE PRESIDENT, DIRECTOR OF RESEARCH, JAMES E. GIBSON, PH.D.
SECRETARY AND ADMINISTRATIVE MANAGER, DONALD A, HART, D.ED.

December 30, 1980

Dr. Joshua Lederberg
President

The Rockerfeller University
New York, NY 10021

Dear Dr. Lederberg,

lyons JZ

SL

CIIT

P.O. BOX 12137
RESEARCH TRIANGLE PARK,
NORTH CAROLINA 27700

(919) 541-2070

Thank you for your note of December 19. Let me again state that it

was a pleasure to visit with you and your colleagues.

I apologize for

not having provided you with copies of our two most recent submissions
when I transmitted the PNAS manuscript. I am still in the embarrassing
position of not having a preprint of the Archives manuscript to send
you, however, I hope to correct that situation as soon as possible. I
may have to send you a copy of the galley proof but have hesitated to

do so because the first galley was in poor shape.

In specific reply to your question, the following concepts and findings
are original to the PNAS manuscript and have not previously been published

or submitted elsewhere:

1) That p-benzoquinone and 1,2,4—benzenetriol inhibit microtubule assembly.

2) That these same compounds inhibit lectin-induced blastogenesis and agglut~

ination.

3) That the mechanism of action is through specific alkylation of critical
sulfhydryl groups (Michael addition) and likely represents the mechanism of
hydroquinone inhibition of microtubule assembly and lymphocyte suppression.

4) The direct comparison of sulfhydryl dependence and reactivity between the

two systems.

5) The concept that differences in quinone chemistry may account for differ-
ences in the pattern of toxicity observed for hydroquinone and catechol.

The basic integrated mechanism has not been pro jposed in our previous

papers nor has the chemistry been detailed before.
press) that hydroquinone inhi

We have published (in
bits microtubule assembly and accelerates
TCBA decay. This work is essentially descriptive and suggests that
GIP-associated sulfhydryls are involved in the process but does not
outline a molecular mechanism.

Similarly, we have submitted a work describing the effects of hydroquinone

on lectin-induced blastogenesis and agglutination. This work does not present
data on p-benzoquinone. A more detailed work is currently in preparation

at this time. These manuscripts refer to the possible connection between
sulfhydryl dependent sites and microtubule integrity, but present no data

on the subject and go no further in outlining a proposed mechanism.

I should also add that the first "formal" exposition of the integrated

mechanism will be at a symposium on "The genotoxic effects of airborne

agents!" to be held at Brookhaven National Laboratory in February. This
will eventually be published in symposium formate I intend to present

the subject in the form of a "mini-review'.

I hope that I have Satisfactorilly answered your question and will endeavor
to get copies of our previously submitted manuscripts to you.

On another subject: I think that I have a couple of examples of advances

in basic understanding in biology that were preceeded by a knowledge and
understanding of the chemistry and effects of a chemical agent. Simply to
outline my selection criteria I should state the well trodden view that

advances in science occur in leaps coincident with the combination of conceptual
integration with technical advances. The use of chemical "probes" provides

a convenience in packaging both conceptual knowledge and technical understanding
of chemical processes into a single focuse However biased I am with respect

to the power of this approach, upon reflection I can think of precious few
examples of its use in the past. As we said before, colchicine is obvious.
Another is acetylcholine. Its synthesis and chemistry were detailed in the
mid-1800's. Its effects on mammalian physiology led ultimately to the definition
of the role of chemieal transmitters in neurobiology.

Another thought I have not yet adequately formulated relates to the use of
agents such as quabain, digitalis and others to characterize important aspects
of both membrane conduction and energy metabolism. It seems to me that a
number of agents were applied as tools in the elucidation of these cellular
processes. I had hoped to research these better before writing you but thought
I'd take this opportunity to suggest these examples,

B “Ky shes,

“Rich Trons