CRC handbook of mammalian metabolism of plant compounds (1991)

523 Pages·2017·37.497 MB·English

by  Scheline, Ronald R

CRC
HANDBOOK
OF
MAMMALIAN METABOLISM
OF
PLANT COMPOUNDS
Author
Ronald R. Scheline
Professor of Biochemical Pharmacology
Department of Pharmacology and Toxicology
School of Medicine
University of Bergen
Bergen, Norway
First published 1991 by CRC Press
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Reissued 2018 by CRC Press
© 1991 by Taylor & Francis
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PREFACE
Because of the widespread and increasing use of foreign compounds (xenobiotics) in many
fields, the understanding of their metabolic fate has assumed growing importance. This subject,
known as xenobiochemistry, has accordingly shown rapid growth during the past four or five
decades. These developments have also resulted in a significant expansion of the relevant
scientific literature including review journals and books. However, much of this information is
topic-oriented rather than compound-oriented and the investigator requiring a convenient
source of information on the metabolic properties of a particular xenobiotic compound often
finds that no summary of these data is available. I have personally felt this need many times in
the course of my studies of xenobiochemistry and this deficiency was a major reason for my
decision to summarize current knowledge on the metabolism of a major group of xenobiotics.
Also instrumental in this decision was the demonstrated value of Professor R. T. Williams’
classic book Detoxication Mechanisms which, although published more than 30 years ago,
remains a useful source of earlier information on the metabolism of specific xenobiotics.
The term plant compounds as used in the present volume can be largely equated with the
phrase secondary plant compounds, i.e., compounds which are apparently not essential to the
functioning of the living plant cell. Accordingly, the text will not deal with the metabolism of
compounds entering into the glycolytic and tricarboxylic acid cycles, and basic nucleotides, the
amino acids of proteins, and the common lipids. Also, attention has been given to compounds
from higher plants rather than from lower classes including algae and fungi. As a general rule
I have deliberately chosen to exclude from the text ancillary material including botanical
sources, pharmacological and toxicological properdes, and other uses of the various com­
pounds. The latter subjects are more readily available in the literature and their inclusion would
unduly increase the length of the book.
I wish to give special thanks to the staff of the University of Bergen library for their assistance
in providing me with many of the required literature references. I would also like to acknowledge
the help of several technical aids which were of immense help to me in the preparation of the
manuscript. These were the Macintosh programs EndNote by Niles and Associates and
Chemlntosh by SoftShell Company. The former program enabled me to manage the several
thousand references in my collection and to prepare the required lists of references. The latter
program was used to make the drawings of the chemical structures including the illustrations of
the metabolic pathways.
Ronald R. Scheline
Bergen, Norway
AUTHOR
Ronald R. Scheline, Ph.D., is Professor of Biochemical Pharmacology in the School of
Medicine at the University of Bergen in Bergen, Norway.
Dr. Scheline received his B.S. degree in pharmacy from the University of California at San
Francisco in 1955. He obtained his Ph.D. degree in pharmaceutical chemistry from the
University of California at San Francisco in 1958. After doing postdoctoral work at St. Mary’s
Medical School, University of London and at the University of Bergen, he was appointed an
Assistant Professor of Pharmacology at the latter institution in 1965. He became Associate
Professor in 1966 and Professor in 1974.
Dr. Scheline is a member of the Norwegian Society of Pharmacology and Toxicology, the
American Chemical Society, and a charter member of the International Society for the Study of
Xenobiotics (ISSX).
Dr. Scheline has published more than 70 research papers in the field of metabolism of foreign
compounds. His major research interests include the influence of the normal gastrointestinal
microflora on the metabolism of xenobiotics and the metabolism of plant compounds in
mammals.
TABLE OF CONTENTS
Metabolism of Hydrocarbons.......................................................................................................1
Aliphatic Hydrocarbons.....................................................................................................................1
Monoterpenoid Hydrocarbons..........................................................................................................4
Acyclic Terpene Hydrocarbons.................................................................................................4
Monocyclic Terpene Hydrocarbons..........................................................................................6
Bicyclic Terpene Hydrocarbons..............................................................................................10
Aromatic Hydrocarbons..................................................................................................................15
References..........................................................................................................................................21
Metabolism of Alcohols................................................................................................................27
Aliphatic Alcohols............................................................................................................................28
Monoterpenoid Alcohols.................................................................................................................33
Acyclic Terpene Alcohols........................................................................................................33
Monocyclic Terpene Alcohols................................................................................................35
Bicyclic Terpene Alcohols.......................................................................................................39
Aromatic Alcohols...........................................................................................................................41
References..........................................................................................................................................44
Metabolism of Phenols and Ethers ...........................................................................................49
Phenols...............................................................................................................................................49
Ethers...................................................................................................................................................61
References..........................................................................................................................................80
Metabolism of Aldehydes, Ketones, and Quinones ..............................................................85
Aldehydes...........................................................................................................................................85
Aliphatic Aldehydes..................................................................................................................85
Monoterpenoid Aldehydes.......................................................................................................86
Acyclic Terpene Aldehydes..............................................................................................86
Monocyclic Terpene Aldehydes........................................................................................87
Bicyclic Terpene Aldehydes.............................................................................................88
Aromatic Aldehydes..................................................................................................................89
Ketones...............................................................................................................................................99
Aliphatic Ketones.......................................................................................................................99
Monoterpenoid Ketones.........................................................................................................103
Monocyclic Terpene Ketones..........................................................................................103
Bicyclic Terpene Ketones...............................................................................................108
Aromatic Ketones.....................................................................................................................113
Quinones...........................................................................................................................................121
Naphthoquinones......................................................................................................................122
Anthraquinones........................................................................................................................122
References........................................................................................................................................130
Metabolism of Acids, Lactones, and Esters .........................................................................139
Acids..................................................................................................................................................139
Aliphatic Acids.........................................................................................................................139
Alicyclic Acids.........................................................................................................................142
Aromatic Acids........................................................................................................................146
Lactones..........................................................................................................................................175
Esters.................................................................................................................................................180
References........................................................................................................................................186
Metabolism of Higher Terpenoids .........................................................................................197
Sesquiterpenoids.............................................................................................................................197
Diterpenoids...................................................................................................................................203
Linear Derivatives...................................................................................................................204
Abietane Derivatives..............................................................................................................206
Kaurane Derivatives...............................................................................................................206
Taxane Derivatives................................................................................................................207
Cassane Derivatives...............................................................................................................207
Other Derivatives....................................................................................................................208
Triterpenoids..................................................................................................................................208
Ursane Derivatives.................................................................................................................209
Oleanane Derivatives.............................................................................................................209
Dammarane Derivatives.........................................................................................................212
Cycloartane Derivatives.........................................................................................................214
Cardiac Steroids......................................................................................................................215
Miscellaneous Steroids...........................................................................................................230
Tetraterpenoids...............................................................................................................................233
References.......................................................................................................................................233
Metabolism of Oxygen Heterocyclic Compounds .............................................................243
Furans..............................................................................................................................................243
Pyrones............................................................................................................................................243
a-Pyrones.................................................................................................................................243
y-Pyrones..................................................................................................................................244
Chroman, Chromene, Chromanone, and Chromone Derivatives..........................................245
Chroman Derivatives..............................................................................................................245
Chromene Derivatives............................................................................................................253
Chromanone Derivatives.......................................................................................................254
Chromone Derivatives............................................................................................................254
Coumarins.......................................................................................................................................255
Coumarin..................................................................................................................................255
Coumarins Containing Hydroxy and/or Methoxy Groups...............................................259
Coumarin Derivatives Containing More Complex Substituents.....................................262
Flavonoids......................................................................................................................................267
Flavones...................................................................................................................................267
Flavonols..................................................................................................................................270
Flavanones................................................................................................................................273
Anthocyanins............................................................................................................................278
Catechins..................................................................................................................................279
Dihydrochalcones and Chalcones........................................................................................284
Isoflavonoids............................................................................................................................287
Xanthones........................................................................................................................................290
Other Oxygen Heterocyclic Compounds..................................................................................291
References.......................................................................................................................................295
Metabolism of Amino Compounds ........................................................................................307
References.......................................................................................................................................330
Metabolism of Nitriles, Nonprotein Amino Acids, Nitro Compounds, Amides,
and Other Aliphatic Nitrogen Compounds.........................................................................337
Nitriles.............................................................................................................................................337
Nonprotein Amino Acids..............................................................................................................342
Nitro Compounds...........................................................................................................................345
Amides.............................................................................................................................................348
Other Aliphatic Nitrogen Compounds........................................................................................352
References........................................................................................................................................353
Metabolism of Nitrogen Heterocyclic Compounds ............................................................357
Pyrrolidine Derivatives.................................................................................................................357
Piperidine Derivatives...................................................................................................................363
Pyridine Derivatives.......................................................................................................................365
Pyrazine Derivatives......................................................................................................................366
Tropane Derivatives.......................................................................................................................367
Indole Derivatives..........................................................................................................................377
Quinoline Derivatives...................................................................................................................393
Isoquinoline Derivatives...............................................................................................................397
Morphinan Derivatives..................................................................................................................405
Py rrolizidine Derivatives...............................................................................................................417
Imidazole Derivatives....................................................................................................................427
Quinolizidine Derivatives.............................................................................................................427
Purine Derivatives..........................................................................................................................429
Other Alkaloids...............................................................................................................................441
References........................................................................................................................................446
Metabolism of Sulfur Compounds..........................................................................................477
Thiols................................................................................................................................................477
Sulfides.............................................................................................................................................478
Disulfides.........................................................................................................................................480
Sulfonium Compounds..................................................................................................................482
Sulfoxides.........................................................................................................................................482
Glucosinolates.................................................................................................................................483
Thiazoles..........................................................................................................................................487
References........................................................................................................................................488
Index ...............................................................................................................................................491

1
METABOLISM OF HYDROCARBONS
ALIPHATIC HYDROCARBONS
Many aliphatic hydrocarbons are found in plants, the most common being long-chain n-
alkanes with the general formula H3C-(CH2)n-CHr The lowest natural member of straight-
chain alkanes is n-pentane, although its higher homologue n-heptane is more common. The
series of plant n-alkanes extends to C35 and it is noteworthy that the odd-numbered members are
much more abundant than are the even-numbered. This fact is apparently related to their
pathway of synthesis which involves decarboxylation of fatty acids with even numbers of carbon
atoms. Branched hydrocarbons are also found, usually in small quantities. Branching commonly
occurs near the end of the chain (methyl group in the b-11-b-28-0001-0300-done ω—1 or ω-2 positions). Many branched-
chain hydrocarbons are acyclic terpenoids. These are based on the isoprene molecule and are
therefore (C5)n-compounds. Although there is no reason to believe that the pathways and
mechanisms involved in the mammalian metabolism of these terpenoid compounds differ
significantly from those involved in the metabolism of other compounds containing similar
chemical groups, terpenoids are grouped separately in this book. A further type of aliphatic
hydrocarbon from plants includes compounds containing unsaturated groups. Olefinic groups
are most common, however a few hydrocarbons containing acetylenic groups are also known.
Considerable interest has been devoted to the mammalian metabolism of several n-alkanes,
with the result that the reaction products and the mechanisms by which they are formed are well
understood in some cases. The report by McCarthy1 appears to have been influential in directing
attention to the possibility of n-alkane metabolism. This study showed that both n-hexadecane
(H3C-(CH2)14-CH3) and n-octadecane (H3C-(CH2)16-CH3) were converted by co-oxidation in
rats and goats to fatty acids of the same chain lengths. These products could then undergo further
reactions including alterations in chain length or incorporation into lipid fractions, especially
liver phospholipids. These metabolic pathways were confirmed in rats given n-octadecane.2
Most of the radioactivity was found in the liver, especially as fatty acids of lecithin, 2 h after
administration of the 1-14C-labeled compound (200 mg/kg, p.o. or i.v.). Respiratory 14C02 was
detected during this period. The localization of the enzymes metabolizing n-hexadecane and the
mechanisms involved have also been investigated. Mitchell and Hübscher3 reported that it was
metabolized via cetyl alcohol (n-hexadecanol) to palmitic acid (n-hexadecanoic acid) by the
mucosa of guinea pig small intestine. Activity was located mainly in the microsomal fraction.
These same reaction products were shown by Kusunose et al.4 to be formed by the microsomal
fraction from mouse liver. Similar fractions from mouse lung or kidney showed little or no
activity, respectively. This investigation indicated that the ω-hydroxylation of n-hexadecane is
catalyzed by a monooxygenase system requiring NADPH and 02. The oxidation of n-
hexadecane was not carried out by the intestinal microflora of rats5 or guinea pigs.3
The metabolism of n-heptadecane (H3C-(CH2)15-CH3) in rats was studied by Tulliez and
Bories6 using 8-14C-labeled material administered in the food. Following a small dose (1 mg),
65% of the radioactivity was lost as respiratory 14C02. Little radioactivity was excreted in the
urine and feces (~1% each) in 6 d. Most of the material remaining in the body was oxidized to
heptadecanoic acid which entered into the normal pathways of fatty acid metabolism including
dehydrogenation to heptadecenoic acid and incorporation into lipids and phospholipids. Tulliez
and Bories,7 in similar feeding experiments with long-chain aliphatic hydrocarbons, reported
that no urinary excretion and little (5 to 10%) fecal excretion occurred with compounds below
C24. Retention of n-alkanes in the body was found with the compounds <C20, however retention
decreased rapidly to zero with higher homologues. Branched-chain compounds showed lower
retention.
Several studies dealing with the in vitro or in vivo metabolism of lower alkanes, including n-
pentane, n-hexane, n-heptane, and n-octane, have been carried out. Hydroxylated derivatives